Mechanisms and Function of Autophagy in Cancer

自噬在癌症中的机制和功能

• 批准号: 10371982
• 负责人: Xuejun Jiang
• 金额: $ 41.8万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371982
• 关键词: Affect; Amino Acids; Animal Model; Autophagocytosis; Biochemical; Biogenesis; Biological; Biological Process; Biology; Calcineurin; Cancer Biology; Cell Aging; Cell Death; Cell Line; Cell Survival; Cell model; Cells; Complex; Conditioned Culture Media; Data; Disease; Environment; FRAP1 gene; Family; Funding; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Glioblastoma; Gliomagenesis; Goals; Grant; Human; Immune; Investigation; Learning; Light; Lysosomes; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Nuclear Import; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Play; Property; Protein Dephosphorylation; Protein Kinase; Protein phosphatase; Regulation; Reporting; Research Proposals; Role; Sampling; Shapes; Signal Transduction; Site; Specificity; Starvation; Stimulus; Stress; Technology; Testing; Therapeutic; anti-cancer; base; cancer cell; cancer therapy; cancer type; clinically relevant; cohort; deep sequencing; experimental study; in vivo; inhibition of autophagy; inhibitor; insight; knock-down; member; mouse model; novel; overexpression; prevent; senescence; stemness; success; temozolomide; transcription factor; transcriptome sequencing; tumor; tumorigenesis; tumorigenic

Mechanisms and Function of Autophagy in Cancer Summary The overall goal of this research proposal is to elucidate the molecular mechanisms of autophagy and its role in cancer. Autophagy is a lysosome-mediated, stress-responsive catabolic pathway that plays important role in both normal biology and disease. Although the core molecular pathway of autophagy has been relatively well delineated, how this pathway is precisely regulated to accomplish specific and sometime seemingly counterintuitive function is not clear. For example, what is the mechanism that enables “autophagy-addicted” cancer cells to possess both intact mTOR activity and high levels of basal autophagy, considering mTOR is a bona fide inhibitor of autophagy? What is the role of autophagy in determining various cell fates such as cell death, senescence, and stemness, which are all relevant to tumorigenesis? What therapeutic implication can we learn from the answers to these basic biological questions concerning autophagy? In the previous funding cycle, we have observed potent anticancer effect of autophagy-inhibition in cellular and mouse models for multiple cancer types, including glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDAC). We discovered that a specific protein phosphatase 2A (PP2A) complex can be stimulated to enhance autophagy initiation through dephosphorylating the autophagy-initiating protein kinase complex, the ULK1 complex, thus counteracting the autophagy-suppressing activity of mTOR. Importantly, our preliminary results indicate that PP2A is also involved in the activation of TFEB transcriptional factor, a master regulator of autophagy gene expression and lysosomal biogenesis. Therefore, via regulating the ULK1 complex and TFEB, PP2A modulates both initiation and potency of autophagy. Intriguingly, we also found that autophagy and TFEB regulate GBM cell senescence under clinically relevant conditions. Based on these preliminary studies, in this grant, we will further investigate the molecular basis of autophagy and its role in cancer, by focusing on the following two aims: (1) the mechanisms by which protein phosphatases regulate TFEB, and the functional impact of such regulation on autophagy and autophagy-addicted cancer cells; and (2) the role of autophagy and TFEB in cancer cell senescence. To achieve these aims, we will conduct experiments that employ a combination of approaches, including standard cellular, molecular and biochemical approaches, animal modeling, and more specialized technologies such as quantitative mass spectrometry and deep sequencing. Success of the proposed study will lead to an in-depth mechanistic understanding of the regulation and function of autophagy in normal biology and cancer biology, and might provide insights into precise targeting of autophagy for cancer treatment. The proposal will also shed light on the functional interplay of autophagy with other important biological processes, including lysosomal biogenesis and senescence.

自噬在癌症中的机制和功能 概括 该研究建议的总体目标是阐明自噬及其的分子机制 在癌症中的作用。自噬是一种溶酶体介导的应力反应分解代谢途径，起着重要的作用 在正常生物学和疾病中的作用。尽管自噬的核心分子途径相对 精心划定的是，如何精确地调节这一途径，以完成特定的特定，有时似乎是 违反直觉功能尚不清楚。例如，什么是实现“自噬成瘾”的机制 癌细胞具有完整的MTOR活性和高水平的基本自噬，考虑到MTOR是一个 自噬的善良抑制剂？自噬在确定各种细胞命运（例如细胞）中的作用是什么 死亡，感应和茎，它们与肿瘤发生有关吗？可以什么治疗意义 我们从这些关于自噬的基本生物学问题的答案中学习？在以前的资金中 循环，我们观察到自噬抑制在细胞和小鼠模型中的潜在抗癌作用 多种癌症类型，包括胶质母细胞瘤（GBM）和胰腺导管腺癌（PDAC）。我们 发现可以刺激特定蛋白质磷酸酶2a（PP2A）复合物以增强自噬 通过去磷酸化的自噬发射蛋白激酶复合物，ULK1复合物的启动，因此 抵消MTOR的自噬抑制活性。重要的是，我们的初步结果表明 PP2A还参与了TFEB转录因子的激活，TFEB转录因子是自噬基因的主要调节剂 表达和溶酶体生物发生。因此，通过调节ULK1复合物和TFEB，PP2A 调节自噬的主动性和效力。有趣的是，我们还发现自噬和TFEB 调节在临床相关条件下的GBM细胞感应。基于这些初步研究，这是 格兰特（Grant），我们将通过专注于自体及其在癌症中的作用进一步研究。 以下两个目的：（1）蛋白质磷酸酶调节TFEB的机制，功能 这种调节对自噬和自噬增添癌细胞的影响； （2）自噬的作用 和癌细胞感应中的TFEB。为了实现这些目标，我们将进行采用 方法的组合，包括标准细胞，分子和生化方法，动物 建模以及更专业的技术，例如定量质谱和深度测序。 拟议的研究的成功将导致对调节的深入机理理解和 自噬在正常生物学和癌症生物学中的功能，并可能提供有关精确靶向的见解 自噬进行癌症治疗。该提案还将阐明自噬的功能相互作用 其他重要的生物学过程，包括溶酶体生物发生和感应。