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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA117742-02
Application #
7275339
Study Section
Special Emphasis Panel (ZRG1-IMM-L (29))
Program Officer
Bini, Alessandra M
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$31,562
Indirect Cost
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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