Mechanisms and Function of Autophagy in Cancer

描述(由申请人提供)：这项研究计划试图调查自噬的分子基础及其在癌症中的作用。自噬是一种细胞分解代谢过程，由独特的细胞内膜运输过程介导，并由溶酶体降解活性执行。它在所有真核细胞中都是保守的，对各种生理事件都是至关重要的。自噬的解除管制是癌症、神经退行性疾病、传染病和心脏疾病等疾病的致病因素。已经证实，一系列自噬特异的基因产物形成了自噬的中心分子途径。然而，仍有许多问题有待回答。例如，在哺乳动物细胞中，中央自噬途径如何感知各种生理和病理触发因素？自噬在癌症发生和治疗中的作用是什么，自噬途径是癌症治疗的潜在靶点吗？最近，我们和其他人发现ULK1-ATG13-FIP200复合体是哺乳动物自噬的重要组成部分，它介导了营养敏感蛋白激酶mTOR的活性。重要的是，我们发现在氨基酸饥饿诱导自噬时，ULK1复合体的激活既需要抑制mTOR，也需要刺激ULK1的特定蛋白磷酸酶。进一步，我们发现多种治疗药物可以刺激培养的胶质母细胞瘤癌细胞的自噬，而RNAi介导的自噬阻断可以增强其中一些治疗药物诱导的胶质母细胞瘤细胞的凋亡。这些结果强调了自噬靶向治疗基底膜的临床潜力，基底膜目前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，在这个计划中，我们将进一步研究自噬的机制及其在癌症中的相关性；我们还将使用胶质母细胞瘤的小鼠模型来研究自噬在肿瘤的启动、维持和治疗中的潜在作用。为了实现这些目标，我们将使用包括分子细胞生物学、生物化学和动物模型在内的多种方法。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。

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.