Therapeutic targeting of stratifin structure and function

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Lack of response to chemo and/or radiation-induced apoptosis is a major problem for successful therapy of human cancers such as pancreatic cancer. Recently, we found that the expression of stratifin is elevated in a series of drug-selected cancer cell lines that are less sensitive to drug-induced apoptosis and its expression level negatively correlates with the drug sensitivity level of these cells. Knocking-down with shRNA and enforced ectopic expression of stratifin both confirmed the cause-effect relationship between stratifin expression and drug insensitivity. The long-term goal of our study is to understand the molecular mechanisms of drug and/or radiation-induced apoptosis in pancreatic cancers and to sensitize cancer cells to these treatment-induced apoptosis. The immediate goal of this study is to investigate the role of stratifin in cellular response to drug or radiation-induced apoptosis and to target stratifin for drug discovery to enhance the response of pancreatic cancer cells to therapeutic treatment. The hypotheses to be tested in this study are that the elevated expression of stratifin in pancreatic cancer cells decreases cellular response to drug or radiation-induced apoptosis by binding to and affecting important proteins for survival and that this effect can be reversed by targeting stratifin using small molecule inhibitors. To this end, four specific aims will be accomplished: (1) to determine if increased stratifin expression also causes decrease in cellular response to radiation-induced apoptosis; (2) to determine if increased stratifin expression regulates Chk2 which, in turn, regulates cell cycle checkpoint for DNA repair and survival; (3) to determine the mechanism of dimerization and if the dimerization is required for the function of stratifin; and (4) to discover and test small chemical compounds targeting stratifin dimerization for chemosensitization. The excellent scientific environment at Indiana University Bren and Melvin Simon Cancer Center, the extensive experience of the principal investigator in studying cellular responses to drug- induced apoptosis, and the generous institutional support will contribute enormously to the likelihood of success of this project. The information and probes obtained from this study will help us understand the role of stratifin in apoptosis in cancer chemotherapy. This work will also lead us to the discovery of therapeutic agents that may help sensitize cancers to drug and radiation therapy and probes for investigating protein-protein interactions. PUBLIC HEALTH RELEVANCE: Lack of response to chemo and radiation treatment-induced apoptosis is a major problem for successful chemotherapy of human pancreatic cancers. The long-term goal of our study is to understand the molecular mechanisms of drug and/or radiation-induced apoptosis in cancers and to sensitize cancer cells to these treatment-induced apoptosis. The hypotheses to be tested in this study are that the elevated expression of stratifin in pancreatic cancer cells decreases cellular response to drug or radiation-induced apoptosis by binding to and affecting important proteins for survival and that this effect can be reversed by targeting stratifin using small molecule inhibitors. To this end, four specific aims will be accomplished: (1) to determine if increased stratifin expression also causes decrease in cellular response to radiation-induced apoptosis; (2) to determine if increased stratifin expression regulates Chk2 which, in turn, regulates cell cycle checkpoint for DNA repair and survival; (3) to determine the mechanism of dimerization and if the dimerization is required for the function of stratifin; and (4) to discover and test small chemical compounds targeting stratifin dimerization for chemosensitization.