'Inefficient autophagy, mitochondrial dysfunction, and pancreatic tumorigenesis

“低效自噬、线粒体功能障碍和胰腺肿瘤发生

• 批准号: 8561430
• 负责人: ANNA S. GUKOVSKAYA
• 金额: $ 20.14万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8561430
• 关键词: Affect; Autophagocytosis; Autophagosome; Calories; Cancer Etiology; Data; Development; Diet; Dietary Factors; Epidemiology; Fatty acid glycerol esters; Genetic; Genetic Predisposition to Disease; Instruction; KRAS2 gene; Life; Lysosomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mitochondria; Mutation; Normal Cell; Oncogenes; Oncogenic; Organ; Organelles; Oxidative Stress; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phosphotransferases; Play; Proteins; Reactive Oxygen Species; Role; Signaling Molecule; Therapeutic Intervention; Time; Tumor Suppressor Proteins; cancer cell; fatty acid oxidation; mitochondrial autophagy; mitochondrial dysfunction; novel; pancreatic tumorigenesis; prevent; tumor; tumorigenesis

PROJECT SUMMARY (See instructions): Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Genetic factors, such as activating mutations in the KRAS oncogene, play a key role in PDAC initiation. Epidemiologic and experimental data indicate that dietary factors, i.e., diet high in fats and calories (HFCD), accelerate tumor development caused by genetic susceptibility. However, the underlying mechanisms remain unclear. Autophagy {macroautophagy) is the principal cellular catabolic pathway in which organelles, e.g., mitochondria, and long-lived proteins are sequestered by autophagosomes and delivered to lysosomes for degradation. The efficiency of autophagic flux is determined by autophagosome formation and lysosomal proteolytic function. Beclini protein is critical to autophagosome formation in normal cells. Accumulating evidence indicates that efficient autophagy acts as a bona fide tumor suppressor mechanism, whereas impaired autophagy is a hallmark of cancer cells. The mechanisms of tumor-suppressive function of autophagy are not fully understood; recent studies indicate that a major role of autophagy is to eliminate dysfunctional mitochondria overproducing reactive oxygen species (ROS), and thus to prevent mutagenic oxidative stress. In this application, we propose a novel mechanism through which HFCD accelerates pancreatic tumorigenesis. Our overall hypothesis is that oncogenic Kras and HFCD act synergistically to impair autophagy and cause mitochondrial dysfunction, in particular, overproduction of reactive oxygen species (ROS). In turn, this results in accumulation of mitochondria overproducing ROS and persistent oxidative stress, promoting tumorigenesis. Importantly, the autophagic and mitochondrial dysfunctions reinforce each other, creating a

项目摘要（参见说明）：胰腺导管腺癌 (PDAC) 是最致命的癌症之一。遗传因素（例如激活 KRAS 癌基因突变）在 PDAC 启动中发挥着关键作用。流行病学和实验数据表明，饮食因素，即高脂肪和高热量饮食（HFCD），会加速遗传易感性引起的肿瘤发展。然而，其根本机制仍不清楚。自噬（宏自噬）是主要的细胞分解代谢途径，其中细胞器（例如线粒体）和长寿命蛋白质被自噬体隔离并递送至溶酶体进行降解。自噬流的效率由自噬体的形成和溶酶体蛋白水解功能决定。 Beclini 蛋白对于正常细胞中自噬体的形成至关重要。越来越多的证据表明，有效的自噬是一种真正的肿瘤抑制机制，而受损的自噬是癌细胞的标志。自噬的抑癌作用机制尚不完全清楚；最近的研究表明，自噬的一个主要作用是消除功能失调的线粒体过度产生活性氧（ROS），从而防止诱变氧化应激。在本申请中，我们提出了一种 HFCD 加速胰腺肿瘤发生的新机制。我们的总体假设是，致癌的 Kras 和 HFCD 协同作用，损害自噬并导致线粒体功能障碍，特别是活性氧 (ROS) 的过度产生。反过来，这会导致线粒体积累过量产生的活性氧和持续的氧化应激，从而促进肿瘤发生。重要的是，自噬和线粒体功能障碍相互加强，从而产生