SUMMARY This proposal is designed to test our novel hypothesis that cellular stress-mediated acid ceramidase (AC) activation, invoked by radiation or chemotherapy, leads to resistance to apoptosis by induction of S1P-S1PR2- mediated AKT activation, leading to nuclear PTEN export. As a corollary, we also hypothesize that targeting AC inhibits S1P/AKT signaling, overcoming cell death resistance in the treatment of prostate cancer. We plan to dissect mechanisms of resistance at the molecular and pharmacological level to develop novel treatment strategies as follows: Specific Aim 1. Determine the mechanisms of AC-dependent resistance to cell death following therapy stress. Specific Aim 2. Determine the therapeutic roles of targeting the AC/SK1/S1P/AKT axis to overcome therapy resistance for the treatment of prostate cancer. Data obtained from these studies will provide novel mechanism-based therapeutic strategies to overcome resistance by targeting AC and/or SK/S1P signaling in solid tumors, including prostate, kidney/bladder and/or liver tumors, which are within the focus of this Program Project.