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

项目一：酸性神经酰胺酶-S1P代谢轴及肿瘤抗凋亡调节

• 批准号: 9980708
• 负责人: CHRISTINA VOELKEL-JOHNSON
• 金额: $ 32.95万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9980708
• 关键词: Apoptosis; Apoptotic; Attenuated; Biochemical; Bladder Neoplasm; Cancer Patient; Cell Death; Cell Nucleus; Cellular Stress; Ceramides; Clinic; Coupled; Data; Development; GTP-Binding Proteins; Generations; Goals; Human; Induction of Apoptosis; Ionizing radiation; Kidney; Link; Lipids; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolism; Modality; Molecular; Nuclear; Nuclear Export; PTEN gene; Pathway interactions; Patients; Pharmacology; Prevention; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Publishing; Radiation; Radiation therapy; Regulation; Relapse; Research Design; Resistance; Role; SPHK1 enzyme; Signal Pathway; Signal Transduction; Solid Neoplasm; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Stress; Testing; Therapeutic; Treatment Failure; Tumor Suppressor Proteins; Up-Regulation; base; cancer therapy; chemotherapy; curative treatments; cytotoxic; design; disorder later incidence prevention; docetaxel; galactosylgalactosylglucosylceramidase; insight; mouse model; novel; novel therapeutic intervention; pre-clinical; prevent; programs; prostate cancer model; resistance mechanism; response; sphingosine 1-phosphate; therapeutic target; therapy resistant; treatment strategy; tumor; urinary

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.

总结 该提议旨在验证我们的新假设，即细胞应激介导的酸性神经酰胺酶（AC） 通过放射或化学疗法引起的活化，通过诱导S1 P-S1 PR 2- 介导的AKT活化，导致核PTEN输出。作为推论，我们还假设， AC抑制S1 P/AKT信号传导，克服前列腺癌治疗中的细胞死亡抗性。我们计划 在分子和药理学水平上剖析耐药机制，以开发新型治疗方法 具体目标如下：1。确定AC依赖性抵抗细胞死亡的机制 治疗压力之后具体目标2。确定靶向AC/SK 1/S1 P/AKT轴的治疗作用 以克服治疗前列腺癌的治疗抗性。从这些研究中获得的数据将 通过靶向AC和/或SK/S1 P提供新的基于机制的治疗策略以克服耐药性 实体瘤中的信号传导，包括前列腺、肾/膀胱和/或肝肿瘤，这些肿瘤是 这个计划项目。