DESCRIPTION (provided by applicant): Induction of prostate cancer (PCa) cell apoptosis can be an effective approach for the chemoprevention and treatment of this disease because clinically PCa is often characterized by low cell proliferation rate and does not respond to standard anti-mitogenic chemotherapy. The goal of this project is to elucidate the biochemical and molecular pathways through which cancer chemopreventive agent selenium (Se) induces P53-dependent, caspase-mediated PCa apoptosis. We hypothesize that wild type P53 tumor suppressor protein and its Ser15 phosphorylation (Ser15P) are crucial determinants for inducing caspase-mediated apoptosis by genotoxic Se metabolites such as selenite and are not critical for apoptosis induced by the non-genotoxic methyl Se. We further hypothesize that selenite exposure induces superoxide generation and DNA strand breaks which trigger P53 Ser15P mediated by ATM and/or ATR protein kinases and signaling to caspase activation. Three specific aims will be accomplished. 1. To establish a causal relationship of selenite induction and/or ATR as the protein kinases for P53 Ser15P. 2. To critically test that caspase-mediated apoptosis by selenite is dependent on wild type P53 and its Ser15P and that apoptosis induced by methyl Se is P53-independent. 3. To delineate the signaling cascade(s) of selenite induction of caspase activation, especially the roles of the mitochondria intrinsic pathway and the death receptor extrinsic pathway. A variety of approaches including enzyme inhibitors, RNA interference of ATM/ATR and P53 and other genetic manipulations will be used. Accomplishing these aims will be crucial for charting a roadmap for studying how Se metabolites selectively bring about the demise of PCa cells depending on their P53 status. The mechanistic insights will help to guide the design of novel Se agents with better efficacy and tolerance and to interpret the results of PCa prevention trials with Se.
|Effective start/end date||9/1/04 → 6/30/09|
- National Institutes of Health: $240,219.00
- National Institutes of Health: $246,000.00
- National Institutes of Health: $266,500.00
- National Institutes of Health: $233,253.00
Tumor Suppressor Protein p53
Death Domain Receptors