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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163200-03
Application #
8712199
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$207,122
Indirect Cost
$72,346
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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