Chapter 2

Sphingomyelin Biosynthesis Modulates Cancer Cell Death and Growth

Elodie Lafont, Kazuyuki Kitatani, Toshiro Okazaki and Bruno Ségui


Resistance to death receptor ligands (such as FasL and TRAIL) and anticancer treatments is a hallmark of cancer cells. Alteration of sphingolipid (SL) metabolism is frequently observed in cancer cells and may contribute to resistance to stress-induced apoptosis. Ceramide, a biologically active sphingolipid, antagonizes cell growth and promotes apoptosis and non-apoptotic forms of cell death. The intracellular levels of ceramide are highly regulated via complex metabolic pathways. Sphingomyelin synthases (SMS) 1 and 2 convert ceramide to sphingomyelin (SM), a ubiquitous phospholipid in mammals. A growing body of evidence in the literature indicates that SMSs likely modulate cell growth and sensitivity to stress-induced apoptosis. On one hand, complete and sustained inhibition of SMS activity likely alters membrane composition and properties through membrane SM depletion, perturbing intracellular signaling pathways and cancer cell growth and conferring partial resistance to death receptor ligands. On the other hand, different patents & reports point to anti-apoptotic functions for SMSs. In patients with chemoresistant leukemia, a decreased intracellular ceramide level was associated with a higher SMS activity. Thus, SMSs and cofactors may constitute original pharmacological targets to treat malignant diseases. This chapter gives an overview on how SM biosynthesis putatively modulates cancer cell death and growth.

Total Pages: 35-62 (28)

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