Mechanisms and Function of Autophagy in Cancer

自噬在癌症中的机制和功能

• 批准号: 8440002
• 负责人: Xuejun Jiang
• 金额: $ 36.69万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440002
• 关键词: Address; Affinity Chromatography; Amino Acids; Animal Model; Animals; Apoptosis; Autophagocytosis; Biochemistry; Birds; Catabolic Process; Cell physiology; Cells; Cellular biology; Clinical; Communicable Diseases; Complex; Coupled; Development; Disease; Enzymes; Eukaryotic Cell; Event; Genes; Glioblastoma; Goals; Grant; Heart Diseases; Human; Intracellular Membranes; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mammalian Cell; Mammals; Mediating; Membrane Protein Traffic; Modeling; Molecular; Molecular and Cellular Biology; Mutation; Neurodegenerative Disorders; Normal Cell; Oncogenic; PTEN gene; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Physiology; Process; Protein Dephosphorylation; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; RAS genes; RNA Interference; Research Proposals; Role; Signal Transduction; Starvation; Stem cells; Therapeutic; Therapeutic Agents; Therapeutic Effect; Work; Xenograft Model; Xenograft procedure; addiction; base; cancer cell; cancer therapy; detection of nutrient; human FRAP1 protein; human disease; in vivo; inhibition of autophagy; insight; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; pre-clinical; public health relevance; screening; therapy development; tumor; tumor initiation; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): This research proposal seeks to investigate the molecular basis of autophagy and its role in cancer. Autophagy is a cellular catabolic process mediated by a unique intracellular membrane trafficking process and executed by lysosomal degrading activity. It is conserved in all eukaryotic cells and crucial for various physiological events. Deregulation of autophagy is a pathogenic factor for diseases including cancer, neurodegenerative disorders, infectious diseases and cardiac diseases. It has been established that a battery of autophagy-specific gene products form a central molecular pathway for autophagy. However, many questions still remain to be answered. For example, in mammalian cells, how does the central autophagy pathway sense various physiological and pathological triggers? What is the role of autophagy in cancer development and treatment, and is autophagy pathway a potential target for cancer therapy? Recently, we and others identified the ULK1-ATG13-FIP200 complex as an essential component of mammalian autophagy that mediates the activity of the nutrient-sensing kinase mTOR. Importantly, we found that upon amino acid starvation-induced autophagy, activation of the ULK1 complex requires both suppression of mTOR and stimulation of a specific protein phosphatase for ULK1. Further, we found that multiple therapeutic agents can stimulate autophagy in cultured glioblastoma cancer cells, and RNAi-mediated autophagy-blockage can potentiate the glioblastoma cell apoptosis induced by some of these therapeutic agents. These results underscore the clinical potential of autophagy-targeting in treatment of GBM, which is currently still a lethal disease with very limited therapeutic options. Built upon these preliminary studies, in this proposal, we will further study the mechanisms of autophagy and its relevance in cancer; we will also use mouse models for glioblastoma to investigate the potential role of autophagy in tumor initiation, maintenance, and treatment. To achieve these goals, we will employ a combination of approaches including molecular cellular biology, biochemistry, and animal modeling. This study will elucidate the molecular basis of mammalian autophagy and its potential therapeutic role in human cancer.

描述（由申请人提供）：该研究提案旨在研究自噬的分子基础及其在癌症中的作用。自噬是一种由独特的细胞内膜运输过程介导的细胞分解代谢过程，并通过溶酶体降解活性执行。它在所有真核细胞中都是保守的，对于各种生理事件至关重要。自噬的放松管制是包括癌症，神经退行性疾病，传染病和心脏疾病在内的疾病的致病因素。已经确定，一系列自噬特异性基因产物构成了自噬的中央分子途径。但是，许多问题仍然有待回答。例如，在哺乳动物细胞中，中央自噬途径如何感觉各种生理和病理触发器？自噬在癌症发育和治疗中的作用是什么，自噬途径是癌症治疗的潜在靶标？最近，我们和其他人将ULK1-ATG13-FIP200复合物鉴定为哺乳动物自噬的重要组成部分，它介导了营养感应激酶MTOR的活性。重要的是，我们发现，在氨基酸饥饿诱导的自噬时，ULK1复合物的激活既需要抑制MTOR，又需要刺激ULK1的特定蛋白质磷酸酶。此外，我们发现多种治疗剂可以刺激培养的胶质母细胞瘤癌细胞中的自噬，而RNAi介导的自噬阻滞可以增强这些治疗剂诱导的胶质母细胞瘤细胞凋亡。这些结果强调了靶向自噬在治疗GBM方面的临床潜力，GBM的治疗仍然是一种致命的疾病，治疗选择非常有限。在这些初步研究的基础上，我们将进一步研究自噬的机制及其在癌症中的相关性。我们还将使用小鼠模型进行胶质母细胞瘤来研究自噬在肿瘤起始，维持和治疗中的潜在作用。为了实现这些目标，我们将采用包括分子细胞生物学，生物化学和动物建模在内的方法组合。这项研究将阐明哺乳动物自噬的分子基础及其在人类癌症中的潜在治疗作用。