Methylselenium and Prostate Cancer Apoptosis
Annual rept. 4 Jan 2003-3 Jan 2004
AMC CANCER RESEARCH CENTER LAKEWOOD CORESEARCH ADMINISTRATION
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The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of PCa cells by methyl selenium Seselenol. We hypothesized that methyl selenium inhibits PI3K-AKT survival pathway leading to the activation of caspase-dependent apoptosis execution in PCa cells. We have so far refined a methylselenol generation system based on methioninase with selenomethionine as substrate Wang et al, Mol. Carcinogenesis, 2002 and studied the association of protein kinases and effects of PI3K inhibitors for apoptosis induction in DU145 cells by methyl Se and selenite Jiang et al, Mol. Cancer Therapeutics, 2002. We compared the apoptosis responses of DU145 androgen independent and mutant p53 and LnCaP androgen dependent, wild type p53 PCa cell lines to methyl Seselenol and to selenite. The LNCaP cells are PTEN mutant and possess high basal AKT activity and are more resistant to apoptosis induction by methyl Se, but was not cross resistant to cell death induction by selenite AACR abstract, 2003. These studies lend additional credence to the role of PI3K-AKT in apoptosis signaling induction by the methyl Se pool. Furthermore, we have discovered a caspase-dependent apoptosis response induced by selenite in LNCaP cells, which is distinct from the lack of caspase involvement in DU145 cells after selenite exposure. This led to a hypothesis that p53 phosphorylation may play a crucial role in mediating apoptosis induced by a genotoxic Se agent through caspase- mediated execution AACR Abstract, 2003. With the anticipation of fund transferred in 2004, we will initiate studies with transfections of mutant kinasesproteins to specifically address their roles in signaling pathways for apoptosis induction by selenium agents.
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