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. Beclin1 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 vicious cycle. Our hypothesis will be tested in 3 Specific Aims.
Aim 1 will determine the effects of oncogenic Kras and HFCD on autophagy and underlying mechanisms.
Aim 2 will determine the effects of oncogenic Kras and HFCD on mitochondrial dysfunction and the underlying mechanisms. In the Aim 3 we will determine the role of impaired autophagy and mitochondrial ROS in tumorigenesis in Kras mice fed HFCD. The proposal will utilize genetically engineered animals, cell culture systems and various biochemical cell biology and microscopy techniques to test the hypotheses.
The project will elucidate the roles of autophagy, and mitochondrial dysfunctions in pancreatic tumorigenesis. The results will suggest novel targets for therapeutic interventions to restore autophagy, decrease oxidative stress, and slow down tumorigenesis. The combined effect of dietary and genetic (Kras mutation) factors on autophagy and mitochondrial function has not been studied in any organ, and the results may also be transferable to the effects of HFCD on tumorigenesis in other organs.
Showing the most recent 10 out of 124 publications
