Accession Number:

ADA478842

Title:

Identification of Novel Retinoid Targets in Prostate Cancer

Descriptive Note:

Final rept. 1 Nov 2004-31 Oct 2007

Corporate Author:

SIDNEY KIMMEL CANCER CENTER SAN DIEGO CA

Personal Author(s):

Report Date:

2007-11-01

Pagination or Media Count:

11.0

Abstract:

Retinoids function upon binding to nuclear retinoid receptors RARs, RXRs and have shown promise for the chemoprevention and treatment of prostate cancer. Novel synthetic retinoid-related molecules RRMs that function as RAR gammabeta-selective agonists MX3350-1, CD2325 or antagonists MX781 were discovered with strong anticancer activity. These RRMs induce apoptosis independently of RARs. The cellular targets that mediate RRM-anticancer activity are unknown and theie mechanism of action is currently under investigation. The main goal of this project was to identify genes that mediate RRM anticancer activity upon selection of Genetic Suppressor Elements GSE that confer resistance to RRM treatment in prostate cancer cells. We have performed several screenings in the presence of toxic amounts of MX781 and MX3350-1. GSEs have been subsequently rescued from surviving cells by PCR amplification using primers specific for the GSE library, followed by DNA sequencing and BLAST homology search for the identification of the corresponding genes. The results of the initial screenings have not been completely reproduced in subsequent experiments and most of the genes tested in functional validation studies have proved to be unnecessary for RRM-induced apoptosis. Our conclusion is that RRMs could activate several independent pathways that converge in apoptosis. Targeting of individual genes may not be sufficient to completely abrogate RRM-mediated cell death.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE