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控

• 批准号: 9072013
• 负责人: CHRISTINA VOELKEL-JOHNSON
• 金额: $ 27.15万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072013
• 关键词: Apoptosis; Apoptotic; Attenuated; Biochemical; Bladder; 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; Prevention; Prostate; 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; 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.

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