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.
Keywords: Anticancer immune response, anticancer treatments, apoptosis,
caspases, cell proliferation, cell death, ceramide, ceramidase, CERT,
chemoresistance, death receptors, glucosylceramide synthase, hematological malignancies, microdomains, plasma membrane, sphingolipids,
sphingolipid metabolism, sphingolipid signaling, sphingomyelinase,
sphingomyelin synthase.
