It has long been apparent that the incidence of cancer at various sites differs between racial and ethnic? groups. In the United States pancreatic cancer (PancCa) incidence is higher in black Americans and? Hispanics than in whites. A growing body of evidence points to high intake of dietary fat as an important? exogenous risk factor in PancCa development. High intake of dietary fat appears to contribute to PancCa? development by driving the production over time of: 1) molecules that enhance cell proliferation and? angiogenesis, and influence inflammation; and 2) reactive oxygen species (ROS) that produce an? Augmented State of Cellular Oxidative Stress (ASCOS) in the pancreas. Pancreatic cells adapt to this? environment by activating stress/survival-signaling pathways that promote resistance to oxidative stressinduced? death. A comprehensive molecular approach to understand the biological basis of the increased? PancCa incidence and mortality is critically needed to eliminate these disparities. Our long-term goal is to? understand the biological basis of these disparities by studying oxidative stress-dependent cellular survival? pathways activated in the pancreas and to develop anticancer therapies capable of bringing relief to this? most deadly of cancers. The focus of this project is survivin, an inhibitor of apoptosis protein (IAP) that has? been found expressed in most cancer types. In pancreatic tumors, survivin is associated with poor? prognosis, progressive disease and shorter patient survival rates. Survivin is expressed in the majority of? pancreatic adenocarcinomas and correlates with cell proliferation and apoptosis resistance. Our hypothesis? is that oxidative stress activates survivin expression promoting pancreatic cancer cell resistance? and 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 in? pancreatic carcinogenesis; (2) characterize in pancreatic cancer, survivin's role in modulating apoptosis? pathways and to more fully characterize survivin T34A-dependent cell killing; and (3) determine the? effectiveness of our dominant negative mutant T34A in eliciting anti-tumor responses in a mouse model of? PancCa. The proposed work is innovative because it focuses on a novel pathway of PancCa cell resistance? to oxidative stress-induced death, mediated by survivin, which could be an important component of the? molecular basis for the disparities in PancCa incidence and mortality. These studies are highly relevant? because they are likely to lead to the preclinical development of novel therapeutic strategies for advanced? PancCa, targeting the lAP-mediated survival pathway. They are also expected to yield valuable information? that could be used for the design of community-participatory preventive interventions aimed at reducing? the disparities in the incidence and mortality of PancCa in the Inland Empire of Southern California.
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