Abstract: Patients with prostate cancer (CaP) develop resistance to conventional therapies and alternative therapies, such as immunotherapy, are being actively considered. TRAIL is selectively cytotoxic to tumor cells and minimally cytotoxic to normal tissues and is a candidate for immunotherapy. CaP cells, however, are resistant to TRAIL due to anti-apoptotic mechanisms such as overexpression of XIAP. This proposal investigated the mechanism by which XIAP regulates resistance to TRAIL and the findings demonstrate that resistance to TRAIL is under the regulation of constitutive active NF-?B activity which regulates the expression of XIAP and the transcription repressor Yin-Yang 1 (YY1) Activation of NF-?P was mediated by TNF-? by an autocrine-paracrine loop. Inhibition of TNF-?, N%-?B, XIAP or YY1 all resulted in the sensitization of TRAIL-resistant CaP cells to TRAIL-induced apoptosis. XIAP inhibits the mitochondrial pathway via activation of caspase 9 whereas YY1 negatively regulates the transcription of the TRAIL receptor DR5. These in vitro studies were corroborated in vivo using CaP tissue microarrays in which both YY1 and XIAP are overexpressed and expressions are elevated as disease progresses and both show prognostic significance. Overall, the findings provide new targets for therapeutic intervention in the reversal of drugs and TRAIL-resistant CaP cells to TRAIL-induced apoptosis.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 15 Dec 2003-14 Dec 2004 |
| Pages: |
160 |
| Report Date: |
JAN 2005 |
| Contract Number: |
DAMD170210023 |
| Report Number: |
A524834 |
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