Prostate cancer (PCa) is the second leading cause of male cancers death in the United States. A major challenge in PCa treatment is the resistance to chemotherapeutic agents through the inhibition of apoptotic pathways by survival proteins. Hence, molecular targeting of these proteins offers an excellent therapeutic opportunity for PCa treatment. Our hypothesis is that molecular targeting of Lens Epithelium Derived Growth Factor/p75 (LEDGF/p75) sensitizes PCa cells to chemotherapy-induced cell death. LEDGF/p75 is a novel survival protein that has been shown by our group to be overexpressed in PCa cell lines and tissues, and promotes PCa cell resistance to death induced by oxidants possibly by upregulating stress proteins such as ERp57.
The specific aims are: 1) To investigate the regulation of ERp57 by LEDGF/p75 in PCa cells; 2) To determine the effects of knockdown of LEDGF/p75 expression in PCa cell sensitivity to oxidant-induced cell death and 3) To examine the effects of LEDGF/p75 knockdown in promoting tumor regression in an in vivo model of PCa. These studies will provide insights into the mechanisms underlying prostate tumor resistance to cell death and lead to development of novel therapeutic strategies for PCa. ? ? ?
| Mediavilla-Varela, Melanie; Pacheco, Fabio J; Almaguel, Frankis et al. (2009) Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75. Mol Cancer 8:68 |
| Brown-Bryan, Terry A; Leoh, Lai S; Ganapathy, Vidya et al. (2008) Alternative splicing and caspase-mediated cleavage generate antagonistic variants of the stress oncoprotein LEDGF/p75. Mol Cancer Res 6:1293-307 |
