Oxidative stress-induced cellular servival pathways in pancreatic cancer

Loma Linda University, Loma Linda CA

Investigators

Linked publications & trials

Abstract

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