Project 1: Acid Ceramidase-S1P Metabolic Axis and Regulation of Tumor Resistance to Apoptosis

摘要 这一建议旨在检验我们的新假设，即细胞应激介导的酸性神经酰胺酶(AC) 放射或化疗引起的激活通过诱导S1P-S1PR2-2而导致对细胞凋亡的抵抗 介导AKT激活，导致核PTEN输出。作为推论，我们还假设目标是 AC抑制S1P/AKT信号转导，在前列腺癌治疗中克服细胞死亡抵抗。我们计划 从分子和药理学水平剖析耐药机制，开发新的治疗方法 策略如下：特定目标1.确定AC依赖的细胞死亡抗性机制 紧随治疗压力。特定目标2.确定靶向AC/SK1/S1P/AKT轴的治疗作用 以克服治疗前列腺癌的治疗阻力。从这些研究中获得的数据将 提供新的基于机制的治疗策略，通过靶向AC和/或SK/S1P来克服耐药性 在实体肿瘤中的信号，包括前列腺癌、肾/膀胱癌和/或肝肿瘤，这些肿瘤位于 此计划项目。

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.