Targeting Sphingolipid Metabolism as a Therapeutic Strategy in Cancer Treatment

Simple Summary Sphingolipids, which are important cell membrane components, have critical roles in regulating cancer cell signaling to control pro-tumoral or antitumoral functions. Ceramide, which is the central sphingolipid, facilitates cancer cell death, while sphingosine-1-phosphate (S1P) induces tumor growth/metastasis and confers resistance to chemo-, immuno-, or radiotherapies. The aim of this review is to highlight the mechanistic strategies of targeting sphingolipid metabolism for cancer therapeutics. Sphingolipids are bioactive molecules that have key roles in regulating tumor cell death and survival through, in part, the functional roles of ceramide accumulation and sphingosine-1-phosphate (S1P) production, respectively. Mechanistic studies using cell lines, mouse models, or human tumors have revealed crucial roles of sphingolipid metabolic signaling in regulating tumor progression in response to anticancer therapy. Specifically, studies to understand ceramide and S1P production pathways with their downstream targets have provided novel therapeutic strategies for cancer treatment. In this review, we present recent evidence of the critical roles of sphingolipids and their metabolic enzymes in regulating tumor progression via mechanisms involving cell death or survival. The roles of S1P in enabling tumor growth/metastasis and conferring cancer resistance to existing therapeutics are also highlighted. Additionally, using the publicly available transcriptomic database, we assess the prognostic values of key sphingolipid enzymes on the overall survival of patients with different malignancies and present studies that highlight their clinical implications for anticancer treatment.