Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence

Sphingolipids are key signaling lipids and their dysregulation has beenassociated with various cellular processes. We have previously shown significantchanges in sphingolipids in therapy-induced senescence, a state of cell cycle arrest as aresponse to chemotherapy, including the accumulation of ceramides, and providedevidence suggesting that ceramide processing is important for this process. Herein, weconducted a focused small molecule inhibitor screen targeting the sphingolipidpathway, which highlighted a new lipid regulator of therapy-induced senescence.Among the inhibitors tested, the inhibition of ceramide kinase by NVP-231 reducedthe levels of senescent cells. Ceramide kinase knockdown exhibited similar effects,strongly supporting the involvement of ceramide kinase during this process. Weshowed that ceramide-1-phosphate was upregulated in therapy-induced senescenceand that NVP-231 reduced ceramide-1-phosphate levels in different cell line models oftherapy-induced senescence. Finally, ceramide-1-phosphate addition to NVP-231-treated cells reversed the effects of NVP-231 during senescence. Overall, our resultsidentify a previously unknown lipid player in therapy-induced senescence and highlight a potential targetable enzyme to reduce thelevels of therapy-induced senescent cells.