Seminars

Sphingolipids have long been known to play important roles in cellular metabolism and membrane biology, but the notion of sphingolipids as cellular signaling molecules has gained recognition only the last two decades. Bioactive sphingolipids, including ceramide, sphingosine and sphingosine 1-phosphate (S1P) are now appreciated as major regulators of multiple cellular processes, including cell proliferation, differentiation, survival, migration and immune responses. Of note, S1P has emerged as a critical lipid mediator promoting tumor cell proliferation, survival, migration and neoangiogenesis. S1P level is low and kept under control throught a delicately regulated balance between its synthesis and its degradation. It has been suggested that the balance between the levels of S1P and its metabolic precursors ceramide and sphingosine provides a rheostat mechanism that decides whether a cell dies (via ceramide and sphingosine) or proliferates and survives (via S1P). Two decisive regulator of this sphingolipid switch are the sphingosine kinase-1 (SphK1), the enzyme converting the death-promoting sphingosine into the growth-promoting S1P and the S1P lyase that degrades S1P irreversibly. SphK1 activity can be stimulated by a wide array of stimuli (e.g. growth factors, hormones) and anticancer treatments cause its down-regulation, and small molecule inhibitors of SphK1 can reduce tumor volume and sensitize to irradiation and chemotherapies in animal models. Much less is known about S1P lyase in cancer. Our recent studies demonstrate a relationship between SphK1-increased activity and concomitant S1P lyase-creased activity in human prostate cancer tissues and relevant clinical features (including aggressiveness and treatment failure) confirming a central role for S1P in prostate cancer that herald promising avenues in risk-assessment and treatment. Finally, current studies conducted in vitro and animals targeting directly S1P by a therapeutic monoclonal anti-S1P antibody are establishing its efficacy as a strong sensitizer to standard treatments including chemotherapy. Phase Ib/II clinical trial in hormone-refractory prostate cancer patients will be conducted in 2012.