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Energy Metabolism and Metabolic Sensors in Stem Cells: The Metabostem Crossroads of Aging and Cancer

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Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 824))

Abstract

We are as old as our adult stem cells are; therefore, stem cell exhaustion is considered a hallmark of aging. Our tumors are as aggressive as the number of cancer stem cells (CSCs) they bear because CSCs can survive treatments with hormones, radiation, chemotherapy, and molecularly targeted drugs, thus increasing the difficulty of curing cancer. Not surprisingly, interest in stem cell research has never been greater among members of the public, politicians, and scientists. But how can we slow the rate at which our adult stem cells decline over our lifetime, reducing the regenerative potential of tissues, while efficiently eliminating the aberrant, life-threatening activity of “selfish”, immortal, and migrating CSCs? Frustrated by the gene-centric limitations of conventional approaches to aging diseases, our group and other groups have begun to appreciate that bioenergetic metabolism, i.e., the production of fuel & building blocks for growth and division, and autophagy/mitophagy, i.e., the quality-control, self-cannibalistic system responsible for “cleaning house” and “recycling the trash”, can govern the genetic and epigenetic networks that facilitate stem cell behaviors. Indeed, it is reasonable to suggest the existence of a “metabostem” infrastructure that operates as a shared hallmark of aging and cancer, thus making it physiologically plausible to maintain or even increase the functionality of adult stem cells while reducing the incidence of cancer and extending the lifespan. This “metabostemness” property could lead to the discovery of new drugs that reprogram cell metabotypes to increase the structural and functional integrity of adult stem cells and positively influence their lineage determination, while preventing the development and aberrant function of stem cells in cancer tissues. While it is obvious that the antifungal antibiotic rapamycin, the polyphenol resveratrol, and the biguanide metformin already belong to this new family of metabostemness-targeting drugs, we can expect a rapid identification of new drug candidates (e.g., polyphenolic xenohormetins) that reverse or postpone “geroncogenesis”, i.e., aging-induced metabolic decline as a driver of tumorigenesis, at the stem cell level.

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References

  1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.

    PubMed Central  PubMed  Google Scholar 

  2. Pollina EA, Brunet A. Epigenetic regulation of aging stem cells. Oncogene. 2011;30:3105–26.

    CAS  PubMed  Google Scholar 

  3. Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing. Nature. 2007;448:767–74.

    CAS  PubMed  Google Scholar 

  4. Rando TA. Stem cells, ageing and the quest for immortality. Nature. 2006;441:1080–6.

    CAS  PubMed  Google Scholar 

  5. Signer RA, Morrison SJ. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell. 2013;12:152–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328–37.

    CAS  PubMed  Google Scholar 

  7. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem. 2013;59:168–79.

    CAS  PubMed  Google Scholar 

  8. Shibata M, Shen MM. The roots of cancer: stemcells and the basis for tumor heterogeneity. Bioessays. 2013;35:253–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Visvader JE. Cells of origin in cancer. Nature. 2011;469:314–22.

    CAS  PubMed  Google Scholar 

  10. Monteiro J, Fodde R. Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur J Cancer. 2010;46:1198–203.

    CAS  PubMed  Google Scholar 

  11. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011;108:7950–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146:633–44.

    CAS  PubMed  Google Scholar 

  13. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A. 2011;108:1397–402.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A. 2013;110:972–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Menendez JA, Alarcón T, Corominas-Faja B, Cuyàs E, López-Bonet E, Martin AG, et al. Xenopatients 2.0: reprogramming the epigenetic landscapes of patient-derived cancer genomes. Cell Cycle. 2014;13(3):358–70.

    CAS  PubMed  Google Scholar 

  16. Mantel C, Broxmeyer HE. Sirtuin 1, stem cells, aging, and stem cell aging. Curr Opin Hematol. 2008;15:326–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Cerletti M, Jang YC, Finley LW, Haigis MC, Wagers AJ. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell. 2012;10:515–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Yilmaz ÖH, Katajisto P, Lamming DW, Gültekin Y, Bauer-Rowe KE, Sengupta S, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012;486:490–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013;494:323–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Park JH, Glass Z, Sayed K, Michurina TV, Lazutkin A, Mineyeva O, et al. Calorie restriction alleviates the age-related decrease in neural progenitor cell division in the aging brain. Eur J Neurosci. 2013;37:1987–93.

    PubMed Central  PubMed  Google Scholar 

  21. Rafalski VA, Mancini E, Brunet A. Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. J Cell Sci. 2012;125:5597–608.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Shyh-Chang N, Daley GQ, Cantley LC. Stem cell metabolism in tissue development and aging. Development. 2013;140:2535–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Mahmoudi S, Brunet A. Aging and reprogramming: a two-way street. Curr Opin Cell Biol. 2012;24:744–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Ochocki JD, Simon MC. Nutrient-sensing pathways and metabolic regulation in stemcells. J Cell Biol. 2013;203:23–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Zhang G, Yang P, Guo P, Miele L, Sarkar FH, Wang Z, et al. Unraveling the mystery of cancer metabolism in the genesis of tumor-initiating cells and development of cancer. Biochim Biophys Acta. 2013;1836:49–59.

    CAS  PubMed  Google Scholar 

  26. Menendez JA, Vellon L, Oliveras-Ferraros C, Cufí S, Vazquez-Martin A. mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle. 2011;10:3658–77.

    CAS  PubMed  Google Scholar 

  27. Guan JL, Simon AK, Prescott M, Menendez JA, Liu F, Wang F, et al. Autophagy in stemcells. Autophagy. 2013;9:830–49.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Pan H, Cai N, Li M, Liu GH, Izpisua Belmonte JC. Autophagic control of cell ‘stemness’. EMBO Mol Med. 2013;5:327–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2:896–917.

    PubMed Central  PubMed  Google Scholar 

  30. Menendez JA, Joven J, Cufí S, Corominas-Faja B, Oliveras-Ferraros C, Cuyàs E, et al. The Warburg effect version 2.0: metabolic reprogramming of cancer stem cells. Cell Cycle. 2013;12:1166–79.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Vazquez-Martin A, López-Bonet E, Cufí S, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, et al. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. Drug Resist Updat. 2011;14:212–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Menendez JA, Joven J, Aragonès G, Barrajón-Catalán E, Beltrán-Debón R, Borrás-Linares I, et al. Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents. Cell Cycle. 2013;12:555–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Blagosklonny MV. Prevention of cancer by inhibiting aging. Cancer Biol Ther. 2008;7:1520–4.

    CAS  PubMed  Google Scholar 

  34. Blagosklonny MV. Aging-suppressants: cellular senescence (hyperactivation) and its pharmacologic deceleration. Cell Cycle. 2009;8:1883–7.

    CAS  PubMed  Google Scholar 

  35. Blagosklonny MV. TOR-driven aging: speeding car without brakes. Cell Cycle. 2009;8:4055–9.

    CAS  PubMed  Google Scholar 

  36. Blagosklonny MV. Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle. 2010;9:683–8.

    CAS  PubMed  Google Scholar 

  37. Blagosklonny MV. Increasing healthy lifespan by suppressing aging in our lifetime: preliminary proposal. Cell Cycle. 2010;9:4788–94.

    CAS  PubMed  Google Scholar 

  38. Blagosklonny MV. Molecular damage in cancer: an argument for mTOR-driven aging. Aging (Albany NY). 2011;3:1130–41.

    CAS  Google Scholar 

  39. Blagosklonny MV. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging (Albany NY). 2012;4:159–65.

    CAS  Google Scholar 

  40. Leontieva OV, Paszkiewicz GM, Blagosklonny MV. Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging. Aging (Albany NY). 2012;4:899–916.

    CAS  Google Scholar 

  41. Blagosklonny MV. MTOR-driven quasi-programmed aging as a disposable soma theory: blind watchmaker vs. intelligent designer. Cell Cycle. 2013;12:1842–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Blagosklonny MV. Rapamycin extends life- and health span because it slows aging. Aging (Albany NY). 2013;5:592–8.

    CAS  Google Scholar 

  43. Blagosklonny MV. Aging is not programmed: Genetic pseudo-program is a shadow of developmental growth. Cell Cycle. 2013;12:3736–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Mariño G, Ugalde AP, Salvador-Montoliu N, Varela I, Quirós PM, Cadiñanos J, et al. Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum Mol Genet. 2008;17:2196–211.

    PubMed  Google Scholar 

  45. Mariño G, López-Otín C. Autophagy and aging: new lessons from progeroid mice. Autophagy. 2008;4:807–9.

    PubMed  Google Scholar 

  46. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Cox LS, Mattison JA. Increasing longevity through caloric restriction or rapamycin feeding in mammals: common mechanisms for common outcomes? Aging Cell. 2009;8:607–13.

    CAS  PubMed  Google Scholar 

  48. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011;10:4230–6.

    CAS  PubMed  Google Scholar 

  50. Mercier I, Camacho J, Titchen K, Gonzales DM, Quann K, Bryant KG, et al. Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. Am J Pathol. 2012;181:278–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Comas M, Toshkov I, Kuropatwinski KK, Chernova OB, Polinsky A, Blagosklonny MV, et al. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53−/− mice by delaying carcinogenesis. Aging (Albany NY). 2012;4:715–22.

    CAS  Google Scholar 

  52. Komarova EA, Antoch MP, Novototskaya LR, Chernova OB, Paszkiewicz G, Leontieva OV, et al. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice. Aging (Albany NY). 2012;4:709–14.

    CAS  Google Scholar 

  53. Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013;123:980–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23:537–48.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  PubMed  Google Scholar 

  57. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Cantor JR, Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2012;2:881–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Galluzzi L, Kepp O, Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov. 2013;12:829–46.

    CAS  PubMed  Google Scholar 

  60. Cufí S, Corominas-Faja B, Lopez-Bonet E, Bonavia R, Pernas S, López IÁ, et al. Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin. Oncotarget. 2013;4:1484–95.

    PubMed Central  PubMed  Google Scholar 

  61. Iglesias-Bartolome R, Gutkind SJ. Exploiting the mTOR paradox for disease prevention. Oncotarget. 2012;3:1061–3.

    PubMed Central  PubMed  Google Scholar 

  62. Anisimov VN. Metformin: do we finally have an anti-aging drug? Cell Cycle. 2013;12:3483–9.

    CAS  PubMed  Google Scholar 

  63. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, et al. Metformin improves health span and lifespan in mice. Nat Commun. 2013;4:2192.

    PubMed Central  PubMed  Google Scholar 

  64. Moiseeva O, Deschênes-Simard X, Pollak M, Ferbeyre G. Metformin, aging and cancer. Aging (Albany NY). 2013;5:330–1.

    Google Scholar 

  65. Anisimov VN. Metformin and rapamycin are master-keys for understanding the relationship between cell senescent, aging and cancer. Aging (Albany NY). 2013;5:337–8.

    CAS  Google Scholar 

  66. Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228–39.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Menendez JA, Joven J. One-carbon metabolism: an aging-cancer crossroad for the gerosuppressant metformin. Aging (Albany NY). 2012;4:894–8.

    CAS  Google Scholar 

  68. Corominas-Faja B, Quirantes-Piné R, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Martin-Castillo B, et al. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY). 2012;4:480–98.

    CAS  Google Scholar 

  69. Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L, et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012;11:23–35.

    CAS  PubMed  Google Scholar 

  70. Berstein LM. Metformin in obesity, cancer and aging: addressing controversies. Aging (Albany NY). 2012;4:320–9.

    CAS  Google Scholar 

  71. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Quirantes R, Segura-Carretero A, Micol V, et al. Metformin lowers the threshold for stress-induced senescence: a role for the microRNA-200 family and miR-205. Cell Cycle. 2012;11:1235–46.

    PubMed  Google Scholar 

  72. Mercken EM, Carboneau BA, Krzysik-Walker SM, de Cabo R. Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev. 2012;11:390–8.

    PubMed Central  PubMed  Google Scholar 

  73. Menendez JA, Cufí S, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Vellon L, et al. Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer. Aging (Albany NY). 2011;3:1063–77.

    CAS  Google Scholar 

  74. Menendez JA, Cufí S, Oliveras-Ferraros C, Vellon L, Joven J, Vazquez-Martin A. Gerosuppressant metformin: less is more. Aging (Albany NY). 2011;3:348–62.

    CAS  Google Scholar 

  75. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, et al. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY). 2011;3:148–57.

    CAS  Google Scholar 

  76. Anisimov VN, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Egormin PA, et al. Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging (Albany NY). 2010;2:945–58.

    CAS  Google Scholar 

  77. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY). 2010;2:760–74.

    CAS  Google Scholar 

  78. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7:2769–73.

    CAS  PubMed  Google Scholar 

  79. Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, et al. Metformin-induced preferential killing of breast cancer initiating CD44 + CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget. 2012;3:395–8.

    PubMed Central  PubMed  Google Scholar 

  80. Vazquez-Martin A, Vellon L, Quirós PM, Cufí S, Ruiz de Galarreta E, Oliveras-Ferraros C, et al. Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells. Cell Cycle. 2012;11:974–89.

    CAS  PubMed  Google Scholar 

  81. Vazquez-Martin A, Cufi S, Lopez-Bonet E, Corominas-Faja B, Oliveras-Ferraros C, Martin-Castillo B, et al. Metformin limits the tumourigenicity of iPS cells without affecting their pluripotency. Sci Rep. 2012;2:964.

    PubMed Central  PubMed  Google Scholar 

  82. Takahashi K, Yamanaka S. Induction of pluripotent stem cell from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    CAS  PubMed  Google Scholar 

  83. Hanna JH, Saha K, Jaenisch R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell. 2010;143:508–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Drews K, Jozefczuk J, Prigione A, Adjaye J. Human induced pluripotent stem cells–from mechanisms to clinical applications. J Mol Med (Berl). 2012;90:735–45.

    Google Scholar 

  85. Ferreira LM, Mostajo-Radji MA. How induced pluripotent stem cells are redefining personalized medicine. Gene. 2013;520:1–6.

    CAS  PubMed  Google Scholar 

  86. Cherry AB, Daley GQ. Reprogrammed cells for disease modeling and regenerative medicine. Annu Rev Med. 2013;64:277–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Liu GH, Ding Z, Izpisua Belmonte JC. iPSC technology to study human aging and aging-related disorders. Curr Opin Cell Biol. 2012;24:765–74.

    CAS  PubMed  Google Scholar 

  88. Tiscornia G, Vivas EL, Izpisúa Belmonte JC. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med. 2011;17:1570–6.

    CAS  PubMed  Google Scholar 

  89. Rohani L, Johnson AA, Arnold A, Stolzing A. The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell. 2014;13:2–7.

    CAS  PubMed  Google Scholar 

  90. Blum B, Benvenisty N. The tumorigenicity of human embryonic stem cells. Adv Cancer Res. 2008;100:133–58.

    PubMed  Google Scholar 

  91. Knoepfler PS. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells. 2009;27:1050–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer. 2011;11:268–77.

    CAS  PubMed  Google Scholar 

  93. Zhang Y, Yao L, Yu X, Ou J, Hui N, Liu S. A poor imitation of a natural process: a call to reconsider the iPSC engineering technique. Cell Cycle. 2012;11:4536–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Barrilleaux B, Knoepfler PS. Inducing iPSCs to escape the dish. Cell Stem Cell. 2011;9:103–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Chen T, Shen L, Yu J, Wan H, Guo A, Chen J, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011;10:908–11.

    CAS  PubMed  Google Scholar 

  96. Easley 4th CA, Ben-Yehudah A, Redinger CJ, Oliver SL, Varum ST, Eisinger VM, et al. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram. 2010;12:263–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Wang Y, Mah N, Prigione A, Wolfrum K, Andrade-Navarro MA, Adjaye J. A transcriptional roadmap to the induction of pluripotency in somatic cells. Stem Cell Rev. 2010;6:282–96.

    CAS  PubMed  Google Scholar 

  98. Li R, Liang J, Ni S, Zhou T, Qing X, Li H, et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010;7:51–63.

    CAS  PubMed  Google Scholar 

  99. Esteban MA, Bao X, Zhuang Q, Zhou T, Qin B, Pei D. The mesenchymal-to-epithelial transition in somatic cell reprogramming. Curr Opin Genet Dev. 2012;22:423–8.

    CAS  PubMed  Google Scholar 

  100. Liu X, Sun H, Qi J, Wang L, He S, Liu J, et al. Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol. 2013;15:829–38.

    CAS  PubMed  Google Scholar 

  101. Lamouille S, Derynck R. Cell size and invasion in TGFbeta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 2007;178:437–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71:3246–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. 2010;12:676–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol. 2013;33:2078–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Jun JI, Lau LF. Cellular senescence controls fibrosis in wound healing. Aging (Albany NY). 2010;2:627–31.

    CAS  Google Scholar 

  106. Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev. 2009;23:2134–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Banito A, Gil J. Induced pluripotent stem cells and senescence: learning the biology to improve the technology. EMBO Rep. 2010;11:353–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009;460:1136–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009;460:1145–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Liu Y, Hoya-Arias R, Nimer SD. The role of p53 in limiting somatic cell reprogramming. Cell Res. 2009;19:1227–8.

    PubMed  Google Scholar 

  111. Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009;460:1140–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature. 2009;462:595–601.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009;460:1149–53.

    PubMed Central  PubMed  Google Scholar 

  114. Son MJ, Son MY, Seol B, Kim MJ, Yoo CH, Han MK, et al. Nicotinamide overcomes pluripotency deficits and reprogramming barriers. Stem Cells. 2013;31:1121–35.

    CAS  PubMed  Google Scholar 

  115. Blagosklonny MV. Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res. 2008;11:801–8.

    CAS  PubMed  Google Scholar 

  116. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008;7:3355–61.

    CAS  PubMed  Google Scholar 

  117. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009;8:1888–95.

    CAS  PubMed  Google Scholar 

  118. Demidenko ZN, Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Cell Cycle. 2009;8:1901–4.

    CAS  PubMed  Google Scholar 

  119. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci U S A. 2010;107:9660–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Demidenko ZN, Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging (Albany NY). 2009;1:1008–16.

    CAS  Google Scholar 

  121. Leontieva OV, Blagosklonny MV. CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle. 2013;12:3063–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–62.

    CAS  PubMed  Google Scholar 

  123. Phadwal K, Watson AS, Simon AK. Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging. Cell Mol Life Sci. 2013;70:89–103.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell. 2011;146:682–95.

    CAS  PubMed  Google Scholar 

  125. Gewirtz DA. Autophagy and senescence in cancer therapy. J Cell Physiol. 2014;229:6–9.

    CAS  PubMed  Google Scholar 

  126. Wang S, Xia P, Ye B, Huang G, Liu J, Fan Z. Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency. Cell Stem Cell. 2013;13:617–25.

    CAS  PubMed  Google Scholar 

  127. He J, Kang L, Wu T, Zhang J, Wang H, Gao H, et al. An elaborate regulation of Mammalian target of rapamycin activity is required for somatic cell reprogramming induced by defined transcription factors. Stem Cells Dev. 2012;21:2630–41.

    CAS  PubMed  Google Scholar 

  128. Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J. The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells. 2010;28:721–33.

    CAS  PubMed  Google Scholar 

  129. Prigione A, Adjaye J. Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. Int J Dev Biol. 2010;54:1729–41.

    PubMed  Google Scholar 

  130. Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 2011;14:264–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Folmes CD, Nelson TJ, Terzic A. Energy metabolism in nuclear reprogramming. Biomark Med. 2011;5:715–29.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Folmes CD, Nelson TJ, Dzeja PP, Terzic A. Energy metabolism plasticity enables stemness programs. Ann N Y Acad Sci. 2012;1254:82–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Panopoulos AD, Yanes O, Ruiz S, Kida YS, Diep D, Tautenhahn R, et al. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res. 2012;22:168–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Folmes CD, Martinez-Fernandez A, Faustino RS, Yamada S, Perez-Terzic C, Nelson TJ, et al. Nuclear reprogramming with c-Myc potentiates glycolytic capacity of derived induced pluripotent stem cells. J Cardiovasc Transl Res. 2013;6:10–21.

    PubMed Central  PubMed  Google Scholar 

  135. Folmes CD, Arrell DK, Zlatkovic-Lindor J, Martinez-Fernandez A, Perez-Terzic C, Nelson TJ, et al. Metabolome and metaboproteome remodeling in nuclear reprogramming. Cell Cycle. 2013;12:2355–65.

    CAS  PubMed  Google Scholar 

  136. Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, et al. HIF1α modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells. 2014;32:364–76.

    CAS  PubMed  Google Scholar 

  137. Bukowiecki R, Adjaye J, Prigione A. Mitochondrial function in pluripotent stemcells and cellular reprogramming. Gerontology. 2013;60:174–82.

    PubMed  Google Scholar 

  138. Ding WX, Yin XM. Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem. 2012;393:547–64.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17:491–506.

    CAS  PubMed  Google Scholar 

  140. Michel S, Wanet A, De Pauw A, Rommelaere G, Arnould T, Renard P. Crosstalk between mitochondrial (dys) function and mitochondrial abundance. J Cell Physiol. 2012;227:2297–310.

    CAS  PubMed  Google Scholar 

  141. Wang K, Klionsky DJ. Mitochondria removal by autophagy. Autophagy. 2011;7:297–300.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Todd LR, Damin MN, Gomathinayagam R, Horn SR, Means AR, Sankar U. Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells. Mol Biol Cell. 2010;21:1225–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Vazquez-Martin A, Cufi S, Corominas-Faja B, Oliveras-Ferraros C, Vellon L, Menendez JA. Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: new insight into the role of mitophagy in cell stemness. Aging (Albany NY). 2012;4:393–401.

    CAS  Google Scholar 

  144. Birket MJ, Orr AL, Gerencser AA, Madden DT, Vitelli C, Swistowski A, et al. A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. J Cell Sci. 2011;124:348–58.

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Zhang J, Khvorostov I, Hong JS, Oktay Y, Vergnes L, Nuebel E, et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J. 2011;30:4860–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Kim JH, Kim HY, Lee YK, Yoon YS, Xu WG, Yoon JK, et al. Involvement of mitophagy in oncogenic K-Ras-induced transformation: overcoming a cellular energy deficit from glucose deficiency. Autophagy. 2011;7:1187–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Kim MJ, Woo SJ, Yoon CH, Lee JS, An S, Choi YH, et al. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem. 2011;286:12924–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Mancias JD, Kimmelman AC. Targeting autophagy addiction in cancer. Oncotarget. 2011;2:1302–6.

    PubMed Central  PubMed  Google Scholar 

  149. Schieke SM, Phillips D, McCoy Jr JP, Aponte AM, Shen RF, Balaban RS, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006;281:27643–52.

    CAS  PubMed  Google Scholar 

  150. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450:736–40.

    CAS  PubMed  Google Scholar 

  151. Dai Y, Zheng K, Clark J, Swerdlow RH, Pulst SM, Sutton JP, et al. Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation. Hum Mol Genet. 2014;23:637–47.

    CAS  PubMed  Google Scholar 

  152. Groenewoud MJ, Zwartkruis FJ. Rheb and mammalian target of rapamycin in mitochondrial homoeostasis. Open Biol. 2013;3:130185.

    PubMed Central  PubMed  Google Scholar 

  153. Li Q, Zhang T, Wang J, Zhang Z, Zhai Y, Yang GY, Sun X. Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke. Biochem Biophys Res Commun. 2014;444:182–8.

    Google Scholar 

  154. Prigione A, Lichtner B, Kuhl H, Struys EA, Wamelink M, Lehrach H, et al. Human induced pluripotent stem cells harbor homoplasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell-like metabolic reprogramming. Stem Cells. 2011;29:1338–48.

    CAS  PubMed  Google Scholar 

  155. Xu X, Duan S, Yi F, Ocampo A, Liu GH, Izpisua Belmonte JC. Mitochondrial regulation in pluripotent stem cells. Cell Metab. 2013;18:325–32.

    CAS  PubMed  Google Scholar 

  156. Vazquez-Martin A, Corominas-Faja B, Cufi S, Vellon L, Oliveras-Ferraros C, Menendez OJ, et al. The mitochondrial H(+)-ATP synthase and the lipogenic switch: new core components of metabolic reprogramming in induced pluripotent stem (iPS) cells. Cell Cycle. 2013;12:207–18.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493:346–55.

    PubMed  Google Scholar 

  158. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–62.

    CAS  PubMed  Google Scholar 

  159. Hardie DG. AMP-activatedprotein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011;25:1895–908.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Hardie DG. Sensing of energy and nutrients by AMP-activatedprotein kinase. Am J Clin Nutr. 2011;93:891S–6.

    CAS  PubMed  Google Scholar 

  161. Shackelford DB, Vasquez DS, Corbeil J, Wu S, Leblanc M, Wu CL, et al. mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci U S A. 2009;106:11137–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17:113–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Dandapani M, Hardie DG. AMPK: opposing the metabolic changes in both tumour cells and inflammatory cells? Biochem Soc Trans. 2013;41:687–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science. 2006;312:1650–3.

    CAS  PubMed  Google Scholar 

  165. Assaily W, Benchimol S. Differential utilization of two ATP-generating pathways is regulated by p53. Cancer Cell. 2006;10:4–6.

    CAS  PubMed  Google Scholar 

  166. Corcoran CA, Huang Y, Sheikh MS. The regulation of energy generating metabolic pathways by p53. Cancer Biol Ther. 2006;5:1610–3.

    CAS  PubMed  Google Scholar 

  167. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126:107–20.

    CAS  PubMed  Google Scholar 

  168. Zawacka-Pankau J, Grinkevich VV, Hünten S, Nikulenkov F, Gluch A, Li H, et al. Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancer. J Biol Chem. 2011;286:41600–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, et al. Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med. 2012;1:811–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Cuezva JM, Sánchez-Aragó M, Sala S, Blanco-Rivero A, Ortega AD. A message emerging from development: the repression of mitochondrial beta-F1-ATPase expression in cancer. J Bioenerg Biomembr. 2007;39:259–65.

    CAS  PubMed  Google Scholar 

  171. López-Ríos F, Sánchez-Aragó M, García-García E, Ortega AD, Berrendero JR, Pozo-Rodríguez F, et al. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res. 2007;67:9013–7.

    PubMed  Google Scholar 

  172. Ortega AD, Sánchez-Aragó M, Giner-Sánchez D, Sánchez-Cenizo L, Willers I, Cuezva JM. Glucose avidity of carcinomas. Cancer Lett. 2009;276:125–35.

    CAS  PubMed  Google Scholar 

  173. Sánchez-Aragó M, Chamorro M, Cuezva JM. Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis. 2010;31:567–76.

    PubMed  Google Scholar 

  174. Sánchez-Cenizo L, Formentini L, Aldea M, Ortega AD, García-Huerta P, Sánchez-Aragó M, et al. Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+−ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem. 2010;285:25308–13.

    PubMed Central  PubMed  Google Scholar 

  175. Sánchez-Aragó M, Formentini L, Martínez-Reyes I, García-Bermudez J, Santacatterina F, Sánchez-Cenizo L, et al. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers. Oncogenesis. 2013;2:e46.

    PubMed Central  PubMed  Google Scholar 

  176. Sánchez-Aragó M, Formentini L, García-Bermúdez J, Cuezva JM. IF1 reprograms energy metabolism and signals the oncogenic phenotype in cancer. Cell Cycle. 2012;11:2963–4.

    PubMed Central  PubMed  Google Scholar 

  177. Sánchez-Aragó M, Formentini L, Cuezva JM. Mitochondria-mediated energy adaption in cancer: the H(+)-ATP synthase-geared switch of metabolism in human tumors. Antioxid Redox Signal. 2013;19:285–98.

    PubMed  Google Scholar 

  178. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763–77.

    CAS  PubMed  Google Scholar 

  179. Menendez JA. Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives. Biochim Biophys Acta. 1801;2010:381–91.

    Google Scholar 

  180. Pandey PR, Xing F, Sharma S, Watabe M, Pai SK, Iiizumi-Gairani M, et al. Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer. Oncogene. 2013;32:5111–22.

    CAS  PubMed  Google Scholar 

  181. Pandey PR, Okuda H, Watabe M, Pai SK, Liu W, Kobayashi A, et al. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase. Breast Cancer Res Treat. 2011;130:387–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Cheema AK, Timofeeva O, Varghese R, Dimtchev A, Shiekh K, Shulaev V, et al. Integrated analysis of ATM mediated gene and protein expression impacting cellular metabolism. J Proteome Res. 2011;10:2651–7.

    CAS  PubMed  Google Scholar 

  183. Ditch S, Paull TT. The ATM protein kinase and cellular redox signaling: beyond the DNA damage response. Trends Biochem Sci. 2012;37:15–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Martin-Castillo B, Menendez JA. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle. 2011;10:1499–501.

    CAS  PubMed  Google Scholar 

  185. Bao B, Wang Z, Ali S, Ahmad A, Azmi AS, Sarkar SH, et al. Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res (Phila). 2012;5:355–64.

    CAS  Google Scholar 

  186. Jung JW, Park SB, Lee SJ, Seo MS, Trosko JE, Kang KS. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One. 2011;6:e28068.

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Hochedlinger K, Yamada Y, Beard C, Jaenisch R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell. 2005;121:465–77.

    CAS  PubMed  Google Scholar 

  188. Peng S, Maihle NJ, Huang Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene. 2010;29:2153–9.

    CAS  PubMed  Google Scholar 

  189. Hu T, Liu S, Breiter DR, Wang F, Tang Y, Sun S. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 2008;68:6533–40.

    CAS  PubMed  Google Scholar 

  190. Kim RJ, Nam JS. OCT4 expression enhances features of cancer stem cells in a mouse model of breast cancer. Lab Anim Res. 2011;27:147–52.

    PubMed Central  PubMed  Google Scholar 

  191. Beltran AS, Rivenbark AG, Richardson BT, Yuan X, Quian H, Hunt JP, et al. Generation of tumor-initiating cells by exogenous delivery of OCT4 transcription factor. Breast Cancer Res. 2011;13:R94.

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Shyh-Chang N, Daley GQ. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell. 2013;12:395–406.

    PubMed Central  PubMed  Google Scholar 

  193. Zhou J, Ng SB, Chng WJ. LIN28/LIN28B: an emerging oncogenic driver in cancer stem cells. Int J Biochem Cell Biol. 2013;45:973–8.

    CAS  PubMed  Google Scholar 

  194. Thornton JE, Gregory RI. How does Lin28 let-7 control development and disease? Trends Cell Biol. 2012;22:474–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Büssing I, Slack FJ, Grosshans H. let-7 microRNAs in development, stem cells and cancer. Trends Mol Med. 2008;14:400–9.

    PubMed  Google Scholar 

  196. Gunaratne PH. Embryonic stem cell microRNAs: defining factors in induced pluripotent (iPS) and cancer (CSC) stem cells? Curr Stem Cell Res Ther. 2009;4:168–77.

    CAS  PubMed  Google Scholar 

  197. Li MA, He L. microRNAs as novel regulators of stem cell pluripotency and somatic cell reprogramming. Bioessays. 2012;34:670–80.

    PubMed Central  PubMed  Google Scholar 

  198. Peter ME. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle. 2009;8:843–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Yang X, Lin X, Zhong X, Kaur S, Li N, Liang S, et al. Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells. Cancer Res. 2010;70:9463–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  200. Oliveras-Ferraros C, Cufí S, Vazquez-Martin A, Torres-Garcia VZ, Del Barco S, Martin-Castillo B, et al. Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a. Cell Cycle. 2011;10:1144–51.

    CAS  PubMed  Google Scholar 

  201. Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, et al. The Lin28/let-7 axis regulates glucose metabolism. Cell. 2011;147:81–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Shinoda G, Shyh-Chang N, Soysa TY, Zhu H, Seligson MT, Shah SP, et al. Fetal deficiency of lin28 programs life-long aberrations in growth and glucose metabolism. Stem Cells. 2013;31:1563–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Shyh-Chang N, Zhu H, Yvanka de Soysa T, Shinoda G, Seligson MT, Tsanov KM, et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell. 2013;155:778–92.

    CAS  PubMed  Google Scholar 

  204. Frost RJ, Olson EN. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci U S A. 2011;108:21075–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  205. Qiu C, Ma Y, Wang J, Peng S, Huang Y. Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic Acids Res. 2010;38:1240–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Ma W, Ma J, Xu J, Qiao C, Branscum A, Cardenas A, et al. Lin28 regulates BMP4 and functions with Oct4 to affect ovarian tumor microenvironment. Cell Cycle. 2013;12:88–97.

    PubMed Central  PubMed  Google Scholar 

  207. Menendez JA, Vazquez-Martin A. Rejuvenating regeneration: metformin activates endogenous adult stem cells. Cell Cycle. 2012;11:3521–2.

    CAS  PubMed Central  PubMed  Google Scholar 

  208. Wu LE, Gomes AP, Sinclair DA. Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis. Cancer Cell. 2014;25:12–9.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was financially supported by the Ministerio de Ciencia e Innovación (SAF2012-38914), Plan Nacional de I + D + I, MICINN, Spain.

Conflict of Interest Statement

The authors of this manuscript have no conflicts of interest to declare.

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Authors and Affiliations

  1. Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Spain

    Javier A. Menendez

  2. Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain

    Javier A. Menendez

  3. Catalan Institute of Oncology, Girona (ICO-Girona), Hospital Dr. Josep Trueta de Girona, Ctra. França s/n, Girona, Catalonia, E-17007, Spain

    Javier A. Menendez

  4. Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan and Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain

    Jorge Joven

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Correspondence to Javier A. Menendez .

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  1. Hospital Universitari de Sant Joan, IISPV, URV, Unitat de Recerca Biomèdica, Reus, Spain

    Jordi Camps

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Menendez, J.A., Joven, J. (2014). Energy Metabolism and Metabolic Sensors in Stem Cells: The Metabostem Crossroads of Aging and Cancer. In: Camps, J. (eds) Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics. Advances in Experimental Medicine and Biology, vol 824. Springer, Cham. https://doi.org/10.1007/978-3-319-07320-0_10

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