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Autophagy and Necroptosis in Cancer

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Cancer Immunology

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Abstract

Autophagy is a process responsible for the turnover of unnecessary or dysfunctional organelles and proteins. It facilitates normal cell growth and development, and it is also a survival pathway, required during starvation or growth factor deprivation. Massive vacuolation as a result of uncontrolled autophagy leads to autophagic cell death. On the other hand, necroptosis is a regulated cell death and shares identical subcellular events with necrosis and secondary necrosis. It is widely postulated that various proteins and pathways related to autophagy and necroptosis signaling are deregulated during cancer development. This chapter highlights the signaling pathways of autophagy and necroptosis and the relevant therapeutic targets in cancer and summarizes the current state of development of novel therapeutics in various phases of clinical trials. In addition, crosstalks in apoptosis, autophagy, and necroptosis signaling pathways and future treatment strategies will be reviewed.

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References

  1. Gao W, Kang J-H, Liao Y, Li M, Yin X-M. Autophagy and cell death. In: Yin X-M, Dong Z, editors. Essential of apoptosis. Pittsburgh: Humana Press; 2009. p. 671–88.

    Google Scholar 

  2. Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J. 1998;17(24):7151–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. de Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.

    PubMed  Google Scholar 

  4. Meijer AJ, Codogno P. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol. 2004;36(12):2445–62.

    CAS  PubMed  Google Scholar 

  5. Lleo A, Invernizzi P, Selmi C, Coppel RL, Alpini G, Podda M, et al. Autophagy: highlighting a novel player in the autoimmunity scenario. J Autoimmun. 2007;29(2–3):61–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6(4):463–77.

    CAS  PubMed  Google Scholar 

  7. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 2005;120(2):237–48.

    CAS  PubMed  Google Scholar 

  8. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6.

    CAS  PubMed  Google Scholar 

  9. Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007;8(11):931–7.

    CAS  PubMed  Google Scholar 

  10. Roy S, Debnath J. Autophagy and tumorigenesis. Semin Immunopathol. 2010;32(4):383–96.

    PubMed Central  PubMed  Google Scholar 

  11. Suzuki K, Ohsumi Y. Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett. 2007;581(11):2156–61.

    CAS  PubMed  Google Scholar 

  12. Ferraro E, Cecconi F. Autophagic and apoptotic response to stress signals in mammalian cells. Arch Biochem Biophys. 2007;462(2):210–9.

    CAS  PubMed  Google Scholar 

  13. Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5(9):726–34.

    CAS  PubMed  Google Scholar 

  14. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12(9):814–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol. 2009;29(1):157–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Ganley IG, du Lam H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284(18):12297–305.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Hara T, Mizushima N. Role of ULK-FIP200 complex in mammalian autophagy: FIP200, a counterpart of yeast Atg17? Autophagy. 2009;5(1):85–7.

    CAS  PubMed  Google Scholar 

  18. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20(7):1992–2003.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Mercer CA, Kaliappan A, Dennis PB. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy. 2009;5(5):649–62.

    CAS  PubMed  Google Scholar 

  20. Simonsen A, Tooze SA. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol. 2009;186(6):773–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72(11):8586–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009;11(4):385–96.

    CAS  PubMed  Google Scholar 

  23. Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell. 2008;19(12):5360–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, et al. Ambra1 regulates autophagy and development of the nervous system. Nature. 2007;447(7148):1121–5.

    CAS  PubMed  Google Scholar 

  25. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672–6.

    CAS  PubMed  Google Scholar 

  26. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol. 2007;9(10):1142–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Ohsumi Y, Mizushima N. Two ubiquitin-like conjugation systems essential for autophagy. Semin Cell Dev Biol. 2004;15(2):231–6.

    CAS  PubMed  Google Scholar 

  28. Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J. 2010;29(11):1792–802.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19(21):5720–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell. 2008;19(5):2092–100.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci. 2004;117(Pt 13):2805–12.

    CAS  PubMed  Google Scholar 

  32. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, et al. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem. 2007;282(52):37298–302.

    CAS  PubMed  Google Scholar 

  33. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007;6(4):304–12.

    CAS  PubMed  Google Scholar 

  34. Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40(2):280–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, et al. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol. 2008;10(7):776–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Liu B, Cheng Y, Liu Q, Bao JK, Yang JM. Autophagic pathways as new targets for cancer drug development. Acta Pharmacol Sin. 2010;31(9):1154–64.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death Differ. 2012;19(1):107–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22.

    CAS  PubMed  Google Scholar 

  39. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res Breast Cancer Res. 2011;13(6):224.

    CAS  Google Scholar 

  40. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol. 2003;4(2):117–26.

    CAS  PubMed  Google Scholar 

  41. Martin KA, Blenis J. Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res. 2002;86:1–39.

    CAS  PubMed  Google Scholar 

  42. Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Mol Med. 2003;9(3–4):65–76.

    PubMed Central  PubMed  Google Scholar 

  43. Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth inhibition. Recent Results Cancer Res. 2007;172:99–124.

    CAS  PubMed  Google Scholar 

  44. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995;270(2):815–22.

    CAS  PubMed  Google Scholar 

  45. Takeuchi H, Kondo Y, Fujiwara K, Kanzawa T, Aoki H, Mills GB, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 2005;65(8):3336–46.

    CAS  PubMed  Google Scholar 

  46. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol Curr Biol. 2004;14(14):1296–302.

    CAS  Google Scholar 

  47. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–89.

    CAS  PubMed  Google Scholar 

  48. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10(3):457–68.

    CAS  PubMed  Google Scholar 

  49. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895–904.

    CAS  PubMed  Google Scholar 

  51. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–75.

    CAS  PubMed  Google Scholar 

  52. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25:903–15.

    CAS  PubMed  Google Scholar 

  54. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122(Pt 20):3589–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Guertin DA, Kim D-H, Sabatini DM. Growth control through the mTOR network. In: Hall MN, et al., editors. Cell growth: control of cell size. Cold Spring Harbor Laboratory Press; New York, 2004. p. 193–234.

    Google Scholar 

  56. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.

    CAS  PubMed  Google Scholar 

  57. Kirken RA, Wang YL. Molecular actions of sirolimus: sirolimus and mTor. Transplant Proc. 2003;35(3 Suppl):227S–30.

    CAS  PubMed  Google Scholar 

  58. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 2010;1804(3):433–9.

    CAS  PubMed  Google Scholar 

  59. Proud CG. Regulation of mammalian translation factors by nutrients. Eur J Biochem. 2002;269(22):5338–49.

    CAS  PubMed  Google Scholar 

  60. Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy. 2009;5(7):973–9.

    CAS  PubMed  Google Scholar 

  61. Galluzzi L, Vicencio JM, Kepp O, Tasdemir E, Maiuri MC, Kroemer G. To die or not to die: that is the autophagic question. Curr Mol Med. 2008;8(2):78–91.

    CAS  PubMed  Google Scholar 

  62. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90.

    CAS  PubMed  Google Scholar 

  63. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activation protein complex toward Rheb. Curr Biol. 2003;13:1259–68.

    CAS  PubMed  Google Scholar 

  64. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med. 2007;13(10):433–42.

    CAS  PubMed  Google Scholar 

  65. Rosner M, Siegel N, Valli A, Fuchs C, Hengstschlager M. mTOR phosphorylated at S2448 binds to raptor and rictor. Amino Acids. 2010;38(1):223–8.

    CAS  PubMed  Google Scholar 

  66. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–8.

    CAS  PubMed  Google Scholar 

  67. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005;11(8):353–61.

    CAS  PubMed  Google Scholar 

  68. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22(2):159–68.

    CAS  PubMed  Google Scholar 

  69. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38.

    PubMed  Google Scholar 

  70. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284(12):8023–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004;306(5698):990–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Kisen GO, Tessitore L, Costelli P, Gordon PB, Schwarze PE, Baccino FM, et al. Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis. 1993;14(12):2501–5.

    CAS  PubMed  Google Scholar 

  73. Toth S, Nagy K, Palfia Z, Rez G. Changes in cellular autophagic capacity during azaserine-initiated pancreatic carcinogenesis. Acta Biol Hung. 2001;52(4):393–401.

    CAS  PubMed  Google Scholar 

  74. Toth S, Nagy K, Palfia Z, Rez G. Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res. 2002;309(3):409–16.

    PubMed  Google Scholar 

  75. Schwarze PE, Seglen PO. Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. Exp Cell Res. 1985;157(1):15–28.

    CAS  PubMed  Google Scholar 

  76. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.

    CAS  PubMed  Google Scholar 

  77. Thompson JE, Thompson CB. Putting the rap on Akt. J Clin Oncol. 2004;22(20):4217–26.

    CAS  PubMed  Google Scholar 

  78. Yu K, Toral-Barza L, Discafani C, Zhang WG, Skotnicki J, Frost P, et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer. 2001;8(3):249–58.

    PubMed  Google Scholar 

  79. Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle (Georgetown Tex). 2009;8(23):3831–7.

    CAS  Google Scholar 

  80. Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004;91(8):1420–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Law BK. Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol. 2005;56(1):47–60.

    PubMed  Google Scholar 

  82. Sorrells DL, Meschonat C, Black D, Li BD. Pattern of amplification and overexpression of the eukaryotic initiation factor 4E gene in solid tumor. J Surg Res. 1999;85(1):37–42.

    CAS  PubMed  Google Scholar 

  83. Easton JB, Houghton PJ. The mTOR pathway and its inhibitors. In: LaRochelle WJ, Shimkets RA, editors. Cancer drug discovery and development: the oncogenomics handbook. Humana Press; New York, 2005. p. 553–70.

    Google Scholar 

  84. Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 2004;23(16):2891–906.

    CAS  PubMed  Google Scholar 

  85. Tan ML, Muhammad TS, Najimudin N, Sulaiman SF. Growth arrest and non-apoptotic programmed cell death associated with the up-regulation of c-myc mRNA expression in T-47D breast tumor cells following exposure to Epipremnum pinnatum (L.) Engl. hexane extract. J Ethnopharmacol. 2005;96(3):375–83.

    CAS  PubMed  Google Scholar 

  86. Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci. 2007;120(Pt 23):4081–91.

    CAS  PubMed  Google Scholar 

  87. Kegel KB, Kim M, Sapp E, McIntyre C, Castano JG, Aronin N, et al. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci Off J Soc Neurosci. 2000;20(19):7268–78.

    CAS  Google Scholar 

  88. Qin ZH, Wang Y, Kegel KB, Kazantsev A, Apostol BL, Thompson LM, et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet. 2003;12(24):3231–44.

    CAS  PubMed  Google Scholar 

  89. Petersen A, Brundin P. Huntington’s disease: the mystery unfolds? Int Rev Neurobiol. 2002;53:315–39.

    CAS  PubMed  Google Scholar 

  90. Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, et al. Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet. 2001;10(12):1243–54.

    CAS  PubMed  Google Scholar 

  91. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol. 1997;12(1):25–31.

    CAS  PubMed  Google Scholar 

  92. Bialik S, Kimchi A. Autophagy and tumor suppression: recent advances in understanding the link between autophagic cell death pathways and tumor development. Adv Exp Med Biol. 2008;615:177–200.

    CAS  PubMed  Google Scholar 

  93. Lee HK, Jones RT, Myers RA, Marzella L. Regulation of protein degradation in normal and transformed human bronchial epithelial cells in culture. Arch Biochem Biophys. 1992;296(1):271–8.

    CAS  PubMed  Google Scholar 

  94. Houri JJ, Ogier-Denis E, De Stefanis D, Bauvy C, Baccino FM, Isidoro C, et al. Differentiation-dependent autophagy controls the fate of newly synthesized N-linked glycoproteins in the colon adenocarcinoma HT-29 cell line. Biochem J. 1995;309(Pt 2):521–7.

    PubMed Central  PubMed  Google Scholar 

  95. Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 2007;67(20):9677–84.

    CAS  PubMed  Google Scholar 

  96. Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, et al. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci. 2008;99(9):1813–9.

    CAS  PubMed  Google Scholar 

  97. Samaddar JS, Gaddy VT, Duplantier J, Thandavan SP, Shah M, Smith MJ, et al. A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol Cancer Ther. 2008;7(9):2977–87.

    CAS  PubMed  Google Scholar 

  98. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90(18):1371–88.

    CAS  PubMed  Google Scholar 

  99. Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, et al. Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst. 2003;95(2):160–5.

    CAS  PubMed  Google Scholar 

  100. Clarke R, Leonessa F, Welch JN, Skaar TC. Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev. 2001;53(1):25–71.

    CAS  PubMed  Google Scholar 

  101. Ariazi EA, Ariazi JL, Cordera F, Jordan VC. Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6(3):181–202.

    CAS  PubMed  Google Scholar 

  102. Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ. 2007;14(3):500–10.

    CAS  PubMed  Google Scholar 

  103. Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB, et al. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat. 2008;112(3):389–403.

    CAS  PubMed  Google Scholar 

  104. Ma XH, Piao S, Wang D, McAfee QW, Nathanson KL, Lum JJ, et al. Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin Cancer Res. 2011;17(10):3478–89.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Investig Drugs. 2008;17(12):1947–54.

    CAS  PubMed  Google Scholar 

  106. Waqar SN, Gopalan PK, Williams K, Devarakonda S, Govindan R. A Phase I Trial of sunitinib and rapamycin in patients with advanced non-small cell lung cancer. Chemotherapy. 2013;59(1):8–13.

    CAS  PubMed  Google Scholar 

  107. Malizzia LJ, Hsu A. Temsirolimus, an mTOR inhibitor for treatment of patients with advanced renal cell carcinoma. Clin J Oncol Nurs. 2008;12(4):639–46.

    PubMed  Google Scholar 

  108. Schwartz GK, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, et al. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2013;14(4):371–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Naing A, Lorusso P, Fu S, Hong D, Chen HX, Doyle LA, et al. Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma. Br J Cancer. 2013;108(4):826–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley 3rd WL, Othus M, et al. Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). Clin Cancer Res. 2012;18(4):1129–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Davies MA, Fox PS, Papadopoulos NE, Bedikian AY, Hwu WJ, Lazar AJ, et al. Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. Clin Cancer Res. 2012;18(4):1120–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Spindler KL, Sorensen MM, Pallisgaard N, Andersen RF, Havelund BM, Ploen J, et al. Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer: outcome and results of KRAS mutational analysis in plasma. Acta Oncol. 2013;52(5):963–70.

    CAS  PubMed  Google Scholar 

  113. Mita MM, Mita A, Rowinsky EK. Mammalian target of rapamycin: a new molecular target for breast cancer. Clin Breast Cancer. 2003;4(2):126–37.

    CAS  PubMed  Google Scholar 

  114. Ray-Coquard I, Favier L, Weber B, Roemer-Becuwe C, Bougnoux P, Fabbro M, et al. Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. Br J Cancer. 2013;108(9):1771–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718–24.

    CAS  PubMed  Google Scholar 

  116. Papadimitrakopoulou VA, Soria JC, Jappe A, Jehl V, Klimovsky J, Johnson BE. Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2012;7(10):1594–601.

    CAS  PubMed  Google Scholar 

  117. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol. 2008;26(3):361–7.

    CAS  PubMed  Google Scholar 

  118. Chawla SP, Staddon AP, Baker LH, Schuetze SM, Tolcher AW, D’Amato GZ, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol. 2012;30(1):78–84.

    CAS  PubMed  Google Scholar 

  119. Keedy VL. Treating metastatic soft-tissue or bone sarcomas – potential role of ridaforolimus. Oncol Targets Ther. 2012;5:153–60.

    Google Scholar 

  120. Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2008;14(9):2756–62.

    CAS  PubMed  Google Scholar 

  121. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7(7):1851–63.

    CAS  PubMed  Google Scholar 

  122. Schnell CR, Stauffer F, Allegrini PR, O’Reilly T, McSheehy PM, Dartois C, et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res. 2008;68(16):6598–607.

    CAS  PubMed  Google Scholar 

  123. Cao P, Maira SM, Garcia-Echeverria C, Hedley DW. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer. 2009;100(8):1267–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68(19):8022–30.

    CAS  PubMed  Google Scholar 

  125. Cohen MH, Johnson JR, Pazdur R. Food and Drug Administration drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. Clin Cancer Res. 2005;11(19 Pt 1):6767–71.

    CAS  PubMed  Google Scholar 

  126. Lefranc F, Facchini V, Kiss R. Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist. 2007;12(12):1395–403.

    CAS  PubMed  Google Scholar 

  127. Katayama M, Kawaguchi T, Berger MS, Pieper RO. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 2007;14(3):548–58.

    CAS  PubMed  Google Scholar 

  128. Yokoyama T, Iwado E, Kondo Y, Aoki H, Hayashi Y, Georgescu MM, et al. Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Ther. 2008;15(17):1233–9.

    CAS  PubMed  Google Scholar 

  129. Milano V, Piao Y, LaFortune T, de Groot J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol Cancer Ther. 2009;8(2):394–406.

    CAS  PubMed  Google Scholar 

  130. Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004;11(4):448–57.

    CAS  PubMed  Google Scholar 

  131. Naumann SC, Roos WP, Jost E, Belohlavek C, Lennerz V, Schmidt CW, et al. Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53. Br J Cancer. 2009;100(2):322–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K. Temozolomide for high grade glioma. Cochrane Database Syst Rev. 2008;4:CD007415.

    PubMed  Google Scholar 

  133. Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27(4):579–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Lou E, Peters KB, Sumrall AL, Desjardins A, Reardon DA, Lipp ES, et al. Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma. Cancer Med. 2013;2(2):185–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Norden AD, Lesser GJ, Drappatz J, Ligon KL, Hammond SN, Lee EQ, et al. Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro Oncol. 2013;15(7):930–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Yust-Katz S, Liu D, Yuan Y, Liu V, Kang S, Groves M, et al. Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma. Cancer. 2013;119(15):2747–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Nghiemphu PL, Wen PY, Lamborn KR, Drappatz J, Robins HI, Fink K, et al. A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys. 2011;81(5):1422–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Wagner L, Turpin B, Nagarajan R, Weiss B, Cripe T, Geller J. Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors. Pediatr Blood Cancer. 2013;60(9):1447–51.

    CAS  PubMed  Google Scholar 

  139. Hummel TR, Wagner L, Ahern C, Fouladi M, Reid JM, McGovern RM, et al. A pediatric Phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a children’s oncology group Phase 1 consortium study. Pediatr Blood Cancer. 2013;60(9):1452–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Kouroussis C, Vamvakas L, Vardakis N, Kotsakis A, Kalykaki A, Kalbakis K, et al. Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a Phase II study. Oncology. 2009;76(2):112–7.

    CAS  PubMed  Google Scholar 

  141. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–91.

    CAS  PubMed  Google Scholar 

  142. Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood. 2009;114(25):5126–35.

    CAS  PubMed  Google Scholar 

  143. Liu N, Tai S, Ding B, Thor RK, Bhuta S, Sun Y, et al. Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis. Endocr Relat Cancer. 2012;19(5):711–23.

    CAS  PubMed  Google Scholar 

  144. Goussetis DJ, Gounaris E, Platanias LC. BCR-ABL1-induced leukemogenesis and autophagic targeting by arsenic trioxide. Autophagy. 2013;9(1):93–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Raja WK, Satti J, Liu G, Castracane J. Dose response of MTLn3 cells to serial dilutions of arsenic trioxide and ionizing radiation. Dose Response Publ Int Hormesis Soc. 2013;11(1):29–40.

    CAS  Google Scholar 

  146. Chiu HW, Ho YS, Wang YJ. Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin. J Mol Med (Berl Germany). 2011;89(9):927–41.

    CAS  Google Scholar 

  147. Cohen KJ, Gibbs IC, Fisher PG, Hayashi RJ, Macy ME, Gore L. A phase I trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood. Neuro Oncol. 2013;15(6):783–7.

    Google Scholar 

  148. Grimm SA, Marymont M, Chandler JP, Muro K, Newman SB, Levy RM, et al. Phase I study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas. J Neurooncol. 2012;110(2):237–43.

    CAS  PubMed  Google Scholar 

  149. Sharma M, Khan H, Thall PF, Orlowski RZ, Bassett Jr RL, Shah N, et al. A randomized phase 2 trial of a preparative regimen of bortezomib, high-dose melphalan, arsenic trioxide, and ascorbic acid. Cancer. 2012;118(9):2507–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013;121(16):3095–102.

    CAS  PubMed  Google Scholar 

  151. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy. 2010;6(3):322–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Shingu T, Fujiwara K, Bogler O, Akiyama Y, Moritake K, Shinojima N, et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int J Cancer. 2009;124(5):1060–71.

    CAS  PubMed  Google Scholar 

  153. Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai K, Okaji Y, et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer. 2010;10:370.

    PubMed Central  PubMed  Google Scholar 

  154. Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol. 2009;625(1–3):220–33.

    CAS  PubMed  Google Scholar 

  155. Kimura T, Takabatake Y, Takahashi A, Isaka Y. Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res. 2013;73(1):3–7.

    CAS  PubMed  Google Scholar 

  156. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005;25(3):1025–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011;17(4):654–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144(5):337–43.

    CAS  PubMed  Google Scholar 

  159. Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, et al. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J Thorac Oncol. 2012;7(10):1602–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Fiers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene. 1999;18(54):7719–30.

    CAS  PubMed  Google Scholar 

  161. Grooten J, Goossens V, Vanhaesebroeck B, Fiers W. Cell membrane permeabilization and cellular collapse, followed by loss of dehydrogenase activity: early events in tumour necrosis factor-induced cytotoxicity. Cytokine. 1993;5(6):546–55.

    CAS  PubMed  Google Scholar 

  162. Higuchi Y. Chromosomal DNA, fragmentation in apoptosis and necrosis induced by oxidative stress. Biochem Pharmacol. 2003;66(8):1527–35.

    CAS  PubMed  Google Scholar 

  163. Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta. 2006;1757(9–10):1371–87.

    CAS  PubMed  Google Scholar 

  164. Proskuryakov SY, Konoplyannikov AG, Gabai VL. Necrosis: a specific form of programmed cell death? Exp Cell Res. 2003;283(1):1–16.

    CAS  PubMed  Google Scholar 

  165. Cocco RE, Ucker DS. Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure. Mol Biol Cell. 2001;12(4):919–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Vanden Berghe T, Kalai M, Denecker G, Meeus A, Saelens X, Vandenabeele P. Necrosis is associated with IL-6 production but apoptosis is not. Cell Signal. 2006;18(3):328–35.

    CAS  PubMed  Google Scholar 

  167. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112–9.

    CAS  PubMed  Google Scholar 

  168. Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol. 2010;22(2):263–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Vercammen D, Vandenabeele P, Beyaert R, Declercq W, Fiers W. Tumour necrosis factor-induced necrosis versus anti-Fas-induced apoptosis in L929 cells. Cytokine. 1997;9(11):801–8.

    CAS  PubMed  Google Scholar 

  170. Wertz IE, Dixit VM. Ubiquitin-mediated regulation of TNFR1 signaling. Cytokine Growth Factor Rev. 2008;19(3–4):313–24.

    CAS  PubMed  Google Scholar 

  171. Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J Biol Chem. 2008;283(36):24295–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, Enwere E, et al. Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A. 2008;105(33):11778–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  173. O’Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol Curr Biol. 2007;17(5):418–24.

    Google Scholar 

  174. Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 2008;30(6):689–700.

    CAS  PubMed  Google Scholar 

  175. Lin Y, Choksi S, Shen HM, Yang QF, Hur GM, Kim YS, et al. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J Biol Chem. 2004;279(11):10822–8.

    CAS  PubMed  Google Scholar 

  176. Knox PG, Davies CC, Ioannou M, Eliopoulos AG. The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas. J Cell Biol. 2011;192(3):391–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 2008;133(4):693–703.

    CAS  PubMed  Google Scholar 

  178. Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135(7):1311–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114(2):181–90.

    CAS  PubMed  Google Scholar 

  180. Lin Y, Devin A, Rodriguez Y, Liu ZG. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13(19):2514–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Feng S, Yang Y, Mei Y, Ma L, Zhu DE, Hoti N, et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 2007;19(10):2056–67.

    CAS  PubMed  Google Scholar 

  182. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1(6):489–95.

    CAS  PubMed  Google Scholar 

  183. Hu WH, Johnson H, Shu HB. Activation of NF-kappaB by FADD, casper, and caspase-8. J Biol Chem. 2000;275(15):10838–44.

    CAS  PubMed  Google Scholar 

  184. Kalai M, Van Loo G, Vanden Berghe T, Meeus A, Burm W, Saelens X, et al. Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA. Cell Death Differ. 2002;9(9):981–94.

    CAS  PubMed  Google Scholar 

  185. Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S. Caspase-independent cell killing by Fas-associated protein with death domain. J Cell Biol. 1998;143(5):1353–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  186. Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med. 1998;187(9):1477–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen GS. RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol Cell. 2011;44(1):9–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Micheau O. Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert Opin Ther Targets. 2003;7(4):559–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem. 2001;276(23):20633–40.

    CAS  PubMed  Google Scholar 

  190. Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J Biol Chem. 2002;277(11):9505–11.

    CAS  PubMed  Google Scholar 

  191. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137(6):1112–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Li J, McQuade T, Siemer Ansgar B, Napetschnig J, Moriwaki K, Hsiao Y-S, et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012;150(2):339–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  193. He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137(6):1100–11.

    CAS  PubMed  Google Scholar 

  194. Cho Y, Challa S, Chan FK. A RNA interference screen identifies RIP3 as an essential inducer of TNF-induced programmed necrosis. Adv Exp Med Biol. 2011;691:589–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Thapa RJ, Basagoudanavar SH, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, et al. NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis. Mol Cell Biol. 2011;31(14):2934–46.

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Vanden Berghe T, Vanlangenakker N, Parthoens E, Deckers W, Devos M, Festjens N, et al. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ. 2010;17(6):922–30.

    CAS  PubMed  Google Scholar 

  197. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325(5938):332–6.

    CAS  PubMed  Google Scholar 

  198. Kim YS, Morgan MJ, Choksi S, Liu ZG. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26(5):675–87.

    CAS  PubMed  Google Scholar 

  199. Moe KT, Aulia S, Jiang F, Chua YL, Koh TH, Wong MC, et al. Differential upregulation of Nox homologues of NADPH oxidase by tumor necrosis factor-alpha in human aortic smooth muscle and embryonic kidney cells. J Cell Mol Med. 2006;10(1):231–9.

    CAS  PubMed  Google Scholar 

  200. Li L, He Q, Huang X, Man Y, Zhou Y, Wang S, et al. NOX3-derived reactive oxygen species promote TNF-alpha-induced reductions in hepatocyte glycogen levels via a JNK pathway. FEBS Lett. 2010;584(5):995–1000.

    CAS  PubMed  Google Scholar 

  201. Yazdanpanah B, Wiegmann K, Tchikov V, Krut O, Pongratz C, Schramm M, et al. Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature. 2009;460(7259):1159–63.

    CAS  PubMed  Google Scholar 

  202. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005;120(5):649–61.

    CAS  PubMed  Google Scholar 

  203. Shen HM, Lin Y, Choksi S, Tran J, Jin T, Chang L, et al. Essential roles of receptor-interacting protein and TRAF2 in oxidative stress-induced cell death. Mol Cell Biol. 2004;24(13):5914–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  204. Xu Y, Huang S, Liu ZG, Han J. Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem. 2006;281(13):8788–95.

    CAS  PubMed  Google Scholar 

  205. Wu W, Liu P, Li J. Necroptosis: an emerging form of programmed cell death. Crit Rev Oncol Hematol. 2012;82(3):249–58.

    PubMed  Google Scholar 

  206. Festjens N, Kalai M, Smet J, Meeus A, Van Coster R, Saelens X, et al. Butylated hydroxyanisole is more than a reactive oxygen species scavenger. Cell Death Differ. 2006;13(1):166–9.

    CAS  PubMed  Google Scholar 

  207. Hayakawa M, Ishida N, Takeuchi K, Shibamoto S, Hori T, Oku N, et al. Arachidonic acid-selective cytosolic phospholipase A2 is crucial in the cytotoxic action of tumor necrosis factor. J Biol Chem. 1993;268(15):11290–5.

    CAS  PubMed  Google Scholar 

  208. Suffys P, Beyaert R, De Valck D, Vanhaesebroeck B, Van Roy F, Fiers W. Tumour-necrosis-factor-mediated cytotoxicity is correlated with phospholipase-A2 activity, but not with arachidonic acid release per se. Eur J Biochem. 1991;195(2):465–75.

    CAS  PubMed  Google Scholar 

  209. Fiore C, Trezeguet V, Le Saux A, Roux P, Schwimmer C, Dianoux AC, et al. The mitochondrial ADP/ATP carrier: structural, physiological and pathological aspects. Biochimie. 1998;80(2):137–50.

    CAS  PubMed  Google Scholar 

  210. Machida K, Hayashi Y, Osada H. A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release by a mitochondrial permeability transition-independent mechanism. J Biol Chem. 2002;277(34):31243–8.

    CAS  PubMed  Google Scholar 

  211. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005;434(7033):652–8.

    CAS  PubMed  Google Scholar 

  212. Temkin V, Huang Q, Liu H, Osada H, Pope RM. Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol Cell Biol. 2006;26(6):2215–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Yamashima T, Kohda Y, Tsuchiya K, Ueno T, Yamashita J, Yoshioka T, et al. Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on ‘calpain-cathepsin hypothesis’. Eur J Neurosci. 1998;10(5):1723–33.

    CAS  PubMed  Google Scholar 

  214. Zhao M, Antunes F, Eaton JW, Brunk UT. Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis. Eur J Biochem. 2003;270(18):3778–86.

    CAS  PubMed  Google Scholar 

  215. Susin SA, Zamzami N, Castedo M, Daugas E, Wang HG, Geley S, et al. The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med. 1997;186(1):25–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, et al. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med. 1995;182(2):367–77.

    CAS  PubMed  Google Scholar 

  217. Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, et al. Mitochondrial control of nuclear apoptosis. J Exp Med. 1996;183(4):1533–44.

    CAS  PubMed  Google Scholar 

  218. Bernardi P. The permeability transition pore. Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. Biochim Biophys Acta. 1996;1275(1–2):5–9.

    PubMed  Google Scholar 

  219. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993;75(2):241–51.

    CAS  PubMed  Google Scholar 

  220. Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, et al. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993;262(5137):1274–7.

    CAS  PubMed  Google Scholar 

  221. Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, et al. AIF deficiency compromises oxidative phosphorylation. EMBO J. 2004;23(23):4679–89.

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert N, et al. Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ. 2005;12(11):1445–8.

    CAS  PubMed  Google Scholar 

  223. Polster BM, Basanez G, Etxebarria A, Hardwick JM, Nicholls DG. Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem. 2005;280(8):6447–54.

    CAS  PubMed  Google Scholar 

  224. Artus C, Boujrad H, Bouharrour A, Brunelle MN, Hoos S, Yuste VJ, et al. AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX. EMBO J. 2010;29(9):1585–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  225. Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, et al. Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol. 2007;27(13):4844–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  226. Cabon L, Galan-Malo P, Bouharrour A, Delavallee L, Brunelle-Navas MN, Lorenzo HK, et al. BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation. Cell Death Differ. 2012;19(2):245–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  227. Xu X, Chua CC, Zhang M, Geng D, Liu CF, Hamdy RC, et al. The role of PARP activation in glutamate-induced necroptosis in HT-22 cells. Brain Res. 2010;1343:206–12.

    CAS  PubMed  Google Scholar 

  228. Declercq W, Takahashi N, Vandenabeele P. Dual face apoptotic machinery: from initiator of apoptosis to guardian of necroptosis. Immunity. 2011;35(4):493–5.

    CAS  PubMed  Google Scholar 

  229. Seya T, Shime H, Takaki H, Azuma M, Oshiumi H, Matsumoto M. TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis. Oncol Immunol. 2012;1(6):917–23.

    Google Scholar 

  230. Osborn SL, Diehl G, Han SJ, Xue L, Kurd N, Hsieh K, et al. Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis. Proc Natl Acad Sci U S A. 2010;107(29):13034–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  231. Li M, Beg AA. Induction of necrotic-like cell death by tumor necrosis factor alpha and caspase inhibitors: novel mechanism for killing virus-infected cells. J Virol. 2000;74(16):7470–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  232. Bonapace L, Bornhauser BC, Schmitz M, Cario G, Ziegler U, Niggli FK, et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest. 2010;120(4):1310–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  233. Horita H, Frankel AE, Thorburn A. Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms. PLoS One. 2008;3(12):e3909.

    PubMed Central  PubMed  Google Scholar 

  234. Mantel F, Frey B, Haslinger S, Schildkopf P, Sieber R, Ott OJ, et al. Combination of ionising irradiation and hyperthermia activates programmed apoptotic and necrotic cell death pathways in human colorectal carcinoma cells. Strahlenther Onkol Organ Dtsch Rontgengesellschaft. 2010;186(11):587–99.

    Google Scholar 

  235. Zhang H, Zhong C, Shi L, Guo Y, Fan Z. Granulysin induces cathepsin B release from lysosomes of target tumor cells to attack mitochondria through processing of bid leading to Necroptosis. J Immunol (Baltimore Md 1950). 2009;182(11):6993–7000.

    CAS  Google Scholar 

  236. Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther. 2007;6(5):1641–9.

    CAS  PubMed  Google Scholar 

  237. Alameda JP, Moreno-Maldonado R, Navarro M, Bravo A, Ramirez A, Page A, et al. An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells. Oncogene. 2010;29(50):6522–32.

    CAS  PubMed  Google Scholar 

  238. Che X, Yang D, Zong H, Wang J, Li X, Chen F, et al. Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients. Urol Oncol. 2012;30(4):450–6.

    CAS  PubMed  Google Scholar 

  239. Munzert G, Kirchner D, Stobbe H, Bergmann L, Schmid RM, Döhner H, et al. Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-κB/Rel–regulated inhibitors of apoptosis. Blood. 2002;100(10):3749–56.

    CAS  PubMed  Google Scholar 

  240. Byrd JC, Kitada S, Flinn IW, Aron JL, Pearson M, Lucas D, et al. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood. 2002;99(3):1038–43.

    CAS  PubMed  Google Scholar 

  241. Schliep S, Decker T, Schneller F, Wagner H, Hacker G. Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia. Exp Hematol. 2004;32(6):556–62.

    CAS  PubMed  Google Scholar 

  242. Loeder S, Zenz T, Schnaiter A, Mertens D, Winkler D, Döhner H, et al. A novel paradigm to trigger apoptosis in chronic lymphocytic leukemia. Cancer Res. 2009;69(23):8977–86.

    CAS  PubMed  Google Scholar 

  243. Zheng M, Morgan-Lappe SE, Yang J, Bockbrader KM, Pamarthy D, Thomas D, et al. Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2. Cancer Res. 2008;68(18):7570–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  244. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 2004;18(11):1272–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  245. Agostinis P, Buytaert E, Breyssens H, Hendrickx N. Regulatory pathways in photodynamic therapy induced apoptosis. Photochem Photobiol Sci Off J Eur Photochem Assoc Eur Soc Photobiol. 2004;3(8):721–9.

    CAS  Google Scholar 

  246. Almeida RD, Manadas BJ, Carvalho AP, Duarte CB. Intracellular signaling mechanisms in photodynamic therapy. Biochim Biophys Acta. 2004;1704(2):59–86.

    CAS  PubMed  Google Scholar 

  247. Madden DT, Egger L, Bredesen DE. A calpain-like protease inhibits autophagic cell death. Autophagy. 2007;3(5):519–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  248. Xu Y, Kim SO, Li Y, Han J. Autophagy contributes to caspase-independent macrophage cell death. J Biol Chem. 2006;281(28):19179–87.

    CAS  PubMed  Google Scholar 

  249. Gonzalez-Polo RA, Boya P, Pauleau AL, Jalil A, Larochette N, Souquere S, et al. The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. J Cell Sci. 2005;118(Pt 14):3091–102.

    CAS  PubMed  Google Scholar 

  250. Tessitore L, Tomasi C, Greco M. Fasting-induced apoptosis in rat liver is blocked by cycloheximide. Eur J Cell Biol. 1999;78(8):573–9.

    CAS  PubMed  Google Scholar 

  251. McLean K, Vandeven NA, Sorenson DR, Daudi S, Liu JR. The HIV protease inhibitor saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells. Gynecol Oncol. 2009;112(3):623–30.

    CAS  PubMed  Google Scholar 

  252. Liu B, Cheng Y, Bian HJ, Bao JK. Molecular mechanisms of Polygonatum cyrtonema lectin-induced apoptosis and autophagy in cancer cells. Autophagy. 2009;5(2):253–5.

    CAS  PubMed  Google Scholar 

  253. Moad AI, Tengku Muhammad TS, Oon CE, Tan ML. Rapamycin induces apoptosis when autophagy is inhibited in T-47D mammary cells and both processes are regulated by Phlda1. Cell Biochem Biophys. 2013;66(3):567–87.

    CAS  PubMed  Google Scholar 

  254. Moretti L, Cha YI, Niermann KJ, Lu B. Switch between apoptosis and autophagy: radiation-induced endoplasmic reticulum stress? Cell Cycle (Georgetown Tex). 2007;6(7):793–8.

    CAS  Google Scholar 

  255. Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 2008;4(5):600–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  256. Williams JA, Thomas AM, Li G, Kong B, Zhan L, Inaba Y, et al. Tissue specific induction of p62/Sqstm1 by farnesoid X receptor. PLoS One. 2012;7(8):e43961.

    CAS  PubMed Central  PubMed  Google Scholar 

  257. Moscat J, Diaz-Meco MT, Wooten MW. Signal integration and diversification through the p62 scaffold protein. Trends Biochem Sci. 2007;32(2):95–100.

    CAS  PubMed  Google Scholar 

  258. Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy. 2010;6(8):1090–106.

    CAS  PubMed Central  PubMed  Google Scholar 

  259. Jin Z, Li Y, Pitti R, Lawrence D, Pham VC, Lill JR, et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell. 2009;137(4):721–35.

    CAS  PubMed  Google Scholar 

  260. Sanz L, Diaz-Meco MT, Nakano H, Moscat J. The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J. 2000;19(7):1576–86.

    CAS  PubMed Central  PubMed  Google Scholar 

  261. Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, et al. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008;13(4):343–54.

    CAS  PubMed  Google Scholar 

  262. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J. 1999;18(11):3044–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  263. Perkins ND. The Rel/NF-kappa B family: friend and foe. Trends Biochem Sci. 2000;25(9):434–40.

    CAS  PubMed  Google Scholar 

  264. Wang Y, Han C, Lu L, Magliato S, Wu T. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology (Baltimore Md). 2013;58(3):995–1010.

    CAS  Google Scholar 

  265. Yin X, Zhang N, Di W. Regulation of LC3-dependent protective autophagy in ovarian cancer cells by protein phosphatase 2A. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2013;23(4):630–41.

    Google Scholar 

  266. Farkas T, Daugaard M, Jaattela M. Identification of small molecule inhibitors of phosphatidylinositol 3-kinase and autophagy. J Biol Chem. 2011;286(45):38904–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  267. Bell BD, Leverrier S, Weist BM, Newton RH, Arechiga AF, Luhrs KA, et al. FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proc Natl Acad Sci U S A. 2008;105(43):16677–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  268. Ch’en IL, Beisner DR, Degterev A, Lynch C, Yuan J, Hoffmann A, et al. Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc Natl Acad Sci U S A. 2008;105(45):17463–8.

    PubMed Central  PubMed  Google Scholar 

  269. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304(5676):1500–2.

    CAS  PubMed  Google Scholar 

  270. Ye YC, Yu L, Wang HJ, Tashiro S, Onodera S, Ikejima T. TNFalpha-induced necroptosis and autophagy via suppression of the p38-NF-kappaB survival pathway in L929 cells. J Pharmacol Sci. 2011;117(3):160–9.

    CAS  PubMed  Google Scholar 

  271. Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, et al. Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med. 2007;13(9):1070–7.

    CAS  PubMed  Google Scholar 

  272. Soria JC, Mark Z, Zatloukal P, Szima B, Albert I, Juhasz E, et al. Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(33):4442–51.

    CAS  PubMed  Google Scholar 

  273. Younes A, Vose JM, Zelenetz AD, Smith MR, Burris HA, Ansell SM, et al. A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin’s lymphoma. Br J Cancer. 2010;103(12):1783–7.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the Ministry of Science, Technology and Innovation Malaysia and Universiti Sains Malaysia.

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Authors and Affiliations

  1. Advanced Medical and Dental Institute, Universiti Sains Malaysia, Persiaran Seksyen 4/9, Bandar Putra Bertam, Kepala Batas, Pulau Pinang, 13200, Malaysia

    Mei Lan Tan PhD

  2. Malaysian Institute of Pharmaceuticals & Nutraceuticals, Ministry of Science, Technology & Innovation (MOSTI), Block 5A, Halaman Bukit Gambir, Minden, Pulau Pinang, 11700, Malaysia

    Mei Lan Tan PhD & Heng Kean Tan Bachelor of Science (Hons)

  3. Department of Medical Laboratories, College of Medicine & Health Sciences, Hodeidah University, Hodeidah, Yemen

    Ahmed Ismail Hassan Moad PhD

  4. Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, 21030, Terengganu, Malaysia

    Tengku Sifzizul Tengku Muhammad PhD

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  1. Mei Lan Tan PhD
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  2. Heng Kean Tan Bachelor of Science (Hons)
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  3. Ahmed Ismail Hassan Moad PhD
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Correspondence to Mei Lan Tan PhD .

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  1. Children's Medical Center Hospital, Tehran University of Medical Sciences Research Center for Immunodeficiencies, Tehran, Iran

    Nima Rezaei

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Tan, M.L., Tan, H.K., Moad, A.I.H., Muhammad, T.S.T. (2015). Autophagy and Necroptosis in Cancer. In: Rezaei, N. (eds) Cancer Immunology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44006-3_14

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