It has long been apparent that the incidence of cancer at various sites differs between racial and ethnicgroups. In the United States pancreatic cancer (PancCa) incidence is higher in black Americans andHispanics than in whites. A growing body of evidence points to high intake of dietary fat as an importantexogenous risk factor in PancCa development. High intake of dietary fat appears to contribute to PancCadevelopment by driving the production over time of: 1) molecules that enhance cell proliferation andangiogenesis, and influence inflammation; and 2) reactive oxygen species (ROS) that produce anAugmented State of Cellular Oxidative Stress (ASCOS) in the pancreas. Pancreatic cells adapt to thisenvironment by activating stress/survival-signaling pathways that promote resistance to oxidative stressinduceddeath. A comprehensive molecular approach to understand the biological basis of the increasedPancCa incidence and mortality is critically needed to eliminate these disparities. Our long-term goal is tounderstand the biological basis of these disparities by studying oxidative stress-dependent cellular survivalpathways activated in the pancreas and to develop anticancer therapies capable of bringing relief to thismost deadly of cancers. The focus of this project is survivin, an inhibitor of apoptosis protein (IAP) that hasbeen found expressed in most cancer types. In pancreatic tumors, survivin is associated with poorprognosis, progressive disease and shorter patient survival rates. Survivin is expressed in the majority ofpancreatic adenocarcinomas and correlates with cell proliferation and apoptosis resistance. Our hypothesisis that oxidative stress activates survivin expression promoting pancreatic cancer cell resistanceand that by targeting survivin for destruction, oxidative stress-induced cell death can be restored.
The specific aims are designed to: (1) characterize oxidative stress-induced survivin and its role inpancreatic carcinogenesis; (2) characterize in pancreatic cancer, survivin's role in modulating apoptosispathways and to more fully characterize survivin T34A-dependent cell killing; and (3) determine theeffectiveness of our dominant negative mutant T34A in eliciting anti-tumor responses in a mouse model ofPancCa. The proposed work is innovative because it focuses on a novel pathway of PancCa cell resistanceto oxidative stress-induced death, mediated by survivin, which could be an important component of themolecular basis for the disparities in PancCa incidence and mortality. These studies are highly relevantbecause they are likely to lead to the preclinical development of novel therapeutic strategies for advancedPancCa, targeting the lAP-mediated survival pathway. They are also expected to yield valuable informationthat could be used for the design of community-participatory preventive interventions aimed at reducingthe disparities in the incidence and mortality of PancCa in the Inland Empire of Southern California.
Showing the most recent 10 out of 85 publications
