'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: 8373928
• 负责人: ANNA S. GUKOVSKAYA
• 金额: $ 21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373928
• 关键词: Affect; Autophagocytosis; Autophagosome; Calories; Cancer Etiology; Data; Development; Diet; Dietary Factors; Epidemiology; Fatty acid glycerol esters; Genetic; KRAS2 gene; Life; Lysosomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mitochondria; Mutation; Normal Cell; Oncogenes; Oncogenic; Organelles; Oxidative Stress; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phosphotransferases; Play; Proteins; Reactive Oxygen Species; Role; Signaling Molecule; Stress; Time; Tumor Suppressor Proteins; cancer cell; fatty acid oxidation; mitochondrial autophagy; mitochondrial dysfunction; novel; pancreatic tumorigenesis; prevent; tumor; tumorigenesis

instmctions): Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Genetic factors, such as activafing mutafions in the KRAS oncogene, play a key role in PDAC initiafion. Epidemiologic and experimental data indicate that dietary factors, i.e., diet high in fats and calories (HFCD), accelerate tumor development caused by genefic suscepfibility. 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 crifical to autophagosome formafion in normal cells. Accumulafing 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 funcfion 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 oxidafive stress. In this applicafion, we propose a novel mechanism through which HFCD accelerates pancreatic tumorigenesis. Our overall hypothesis is that oncogenic Kras and HFCD act synergysfically 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 oxidafive stress, promofing tumorigenesis. Importantly, the autophagic and mitochondrial dysfunctions reinforce each other, creating a

说明）： 胰腺导管腺癌（PDAC）是最致命的癌症之一。遗传因素，如 激活KRAS癌基因突变，在PDAC的启动中起关键作用。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），加速肿瘤 由遗传的可移植性引起的发展。然而，其潜在机制仍不清楚。 自噬（macroautophagy）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被递送到溶酶体， 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Beclini蛋白是正常细胞中自噬体形成的关键蛋白。阿古库拉芬 有证据表明，有效的自噬作为一种真正的肿瘤抑制机制，而 受损的自噬是癌细胞的标志。本文探讨了人肝癌细胞系的抑瘤作用机制 自噬还没有完全理解;最近的研究表明，自噬的主要作用是消除 功能失调的线粒体过度产生活性氧（ROS），从而防止诱变 氧化应激在这个应用中，我们提出了一种新的机制，通过它HFCD加速 胰腺肿瘤发生我们的总体假设是致癌Kras和HFCD协同作用， 损害自噬并引起线粒体功能障碍，特别是活性氧过度产生 物种（ROS）。反过来，这导致线粒体积累过量产生ROS，并持续存在。 氧化应激，促进肿瘤发生。重要的是，自噬和线粒体功能障碍 相互促进，创造一个