'Inefficient autophagy, mitochondrial dysfunction, and pancreatic tumorigenesis

说明)： 胰腺导管腺癌(PDAC)是最致命的癌症之一。遗传因素，例如 KRAS癌基因突变子的激活在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，即高脂肪和高卡路里饮食(HFCD)，会加速肿瘤 由遗传易感性引起的发育。然而，潜在的机制仍不清楚。 自噬是细胞分解代谢的主要途径，在该途径中，细胞器，例如， 线粒体和长寿蛋白被自噬小体隔离，并被运送到溶酶体内 退化。自噬通量的效率由自噬小体的形成和溶酶体决定。 蛋白分解功能。在正常细胞中，Beclini蛋白对自噬小体的形成至关重要。累积黄曲霉毒素 有证据表明，有效的自噬是一种真正的肿瘤抑制机制，而 自噬功能受损是癌细胞的一个特征。人参皂苷抑瘤作用机制的研究 自噬还没有被完全理解；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。在这一应用中，我们提出了一种新的机制，通过它来加速HFCD 胰腺肿瘤的发生。我们的总体假设是致癌的Kras和HFCD协同作用于 损害自噬并导致线粒体功能障碍，特别是产生过多的活性氧。 种(ROS)。反过来，这会导致线粒体积累过量产生的ROS和持久性 氧化应激，促进肿瘤发生。重要的是，自噬和线粒体功能障碍 相辅相成，创造

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