Role of SPTSSB-regulated de novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling

Summary Anti-androgens are a common therapy in prostate cancer (PCa) targeting Androgen Receptor (AR) signaling. However, these therapies fail due to selection of highly aggressive AR-negative cancer cells that have no therapeutic options available. We demonstrate that elevating endogenous ceramide levels with administration of exogenous Ceramide Nanoliposomes (CNL) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reduced de novo sphingolipid synthesis in AR-positive cells. We show that anti-androgens elevate de novo generation of sphingolipids via SPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells through de novo synthesis, while SPTSSB knockdown limited CNL’s efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is up-regulated in advanced PCa patients after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic.