Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in
cancer, which is becoming the deadliest disease in the world. These
lipid molecules have also been implicated in the mechanism of action of
cancer chemotherapeutics.
Ceramide, the central molecule of
sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. Interestingly, recent studies suggest de novo-generated
ceramides may have distinct and opposing roles in the promotion/suppression of
tumors, and that these activities are based on their
fatty acid chain lengths, subcellular localization and/or direct downstream targets. For example, in
head and neck cancer cells,
ceramide synthase 6/C(16)-
ceramide addiction was revealed, and this was associated with increased
tumor growth, whereas downregulation of its synthesis resulted in ER stress-induced apoptosis. By contrast,
ceramide synthase 1-generated C(18)-ceramide has been shown to suppress
tumor growth in various
cancer models, both in situ and in vivo. In addition,
ceramide metabolism to generate
sphingosine-1-phosphate (S1P) by
sphingosine kinases 1 and 2 mediates, with or without the involvement of
G-protein-coupled
S1P receptor signaling, prosurvival, angiogenesis,
metastasis and/or resistance to
drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which
sphingolipid metabolism and signaling regulate
tumor growth and progression, such as identifying direct intracellular
protein targets of
sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated
ceramides by
ceramide synthases and/or S1P in the regulation of
cancer pathogenesis, as well as the development of
sphingolipid-based
cancer therapeutics and drug resistance.