摘要：SummaryAnti-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 (CNLs) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reducedde novosphingolipid synthesis in AR-positive cells. We show that anti-androgens elevatede novogeneration of sphingolipids viaSPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells throughde novosynthesis, while SPTSSB knockdown limited CNL's efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is upregulated in patients with advanced PCa after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic.Graphical AbstractDisplay OmittedHighlights•AR-negative PCa cells are more susceptible to CNL than AR-positive cells•Combination of anti-androgens and CNL results in enhanced efficacy for AR-positive PCa•AR negatively regulates thede novosynthesis of sphingolipids through SPTSSB•SPTSSB is crucial for CNL effect in AR-negative PCa and is upregulated in neuroendocrine tumorsCell Biology; Cancer
