'Inefficient autophagy, mitochondrial dysfunction, and pancreatic tumorigenesis

项目摘要(见说明)：胰腺导管腺癌(PDAC)是最致命的癌症之一。遗传因素，如KRAS癌基因的激活突变，在PDAC的启动中起着关键作用。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)，加速了由遗传易感性引起的肿瘤的发展。然而，潜在的机制仍不清楚。自噬是主要的细胞分解代谢途径，其中细胞器，如线粒体和长寿蛋白被自噬小体隔离，并被运送到溶酶体进行降解。自噬通量的效率取决于自噬小体的形成和溶酶体的蛋白分解功能。Beclini蛋白对正常细胞自噬小体的形成至关重要。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，而自噬受损是癌细胞的标志。自噬抑制肿瘤的机制还不完全清楚；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物种(ROS)，从而防止突变性氧化应激。在这一应用中，我们提出了一种新的机制，通过HFCD加速胰腺肿瘤的发生。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，特别是活性氧物种(ROS)的过度产生。反过来，这会导致线粒体积累过量产生的ROS和持续的氧化应激，促进肿瘤的发生。重要的是，自噬和线粒体功能障碍相互加强，创造了一种

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