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Neutral Sphingomyelinase 2: Structure, Function, and Regulation with Emphasis on Nitric Oxide Involvement and Potential Implications for Cancer Therapy

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Nitric Oxide and Cancer: Pathogenesis and Therapy

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Abstract

Mammalian neutral sphingomyelinase 2 is encoded by the gene smpd3 and belongs to the family of hydrolases which catalyze the breakdown of sphingomyelin to form ceramide and phosphocholine. The bioactive ceramide can then act as the second messenger molecule capable of mediating an array of cellular events, such as growth arrest and apoptosis. Recent studies have revealed that the expression and activity of neutral sphingomyelinase 2 are selectively regulated and this regulation can take place at the transcriptional level as well as at the post-translational level. Upon exposure to oxidative stress, endoplasmic reticulum stress, tumour necrosis factor alpha stimulation or anti-cancer drugs, altered neutral sphingomyelinase 2 activity directly translates into changes in ceramide levels which help cells mount an appropriate response. On the other hand, inappropriate activation or inhibition of neutral sphingomyelinase 2 could contribute to the development of pathological conditions such as cancer and endothelial dysfunction. In this chapter, we focus on current knowledge regarding neutral sphingomyelinase 2 structure, the regulation of its activity, its function and potential involvement in stress response and cancer genesis.

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Abbreviations

APL:

Anionic phospholipid

ATRA:

All-trans retinoic acid

BAEC:

Bovine aortic endothelial cells

EED:

Embryonic ectodermal development

eNOS:

Endothelial nitric oxide synthase

iNOS:

Inducible nitric oxide synthase

nNOS:

Neuronal nitric oxide synthase

ER:

Endoplasmic reticulum

HAEC:

Human airway epithelial cells

HEK:

Human embryonic kidney

HSP:

Heat shock protein

MAPK:

Mitogen activated protein kinase

PKC:

Protein kinase C

ROS:

Reactive oxygen species

SM:

Sphingomyelin

SMase:

Sphingomyelinase

TNF:

Tumour necrosis factor

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Acknowledgements

BM research related to this chapter is supported by grants from Seeds4Hope and Natural Sciences and Engineering Research Council (NSERC).

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No potential conflicts of interest are disclosed.

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Authors and Affiliations

  1. Department of Chemistry & Biochemistry, University of Windsor, 273-1 Essex Hall, 401 Sunset Ave., N9B 3P4, Windsor, ON, Canada

    Bei Lei Sun & Bulent Mutus

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Correspondence to Bulent Mutus .

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  1. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California of Los Angeles, Los Angeles, California, USA

    Benjamin Bonavida

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Sun, B., Mutus, B. (2015). Neutral Sphingomyelinase 2: Structure, Function, and Regulation with Emphasis on Nitric Oxide Involvement and Potential Implications for Cancer Therapy. In: Bonavida, B. (eds) Nitric Oxide and Cancer: Pathogenesis and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-13611-0_18

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