Accession Number:

ADA413411

Title:

Fatty Acid Synthesis and Prostate Cancer: Hormonal Regulation and Anti-Metabolite targeting of an Acquired Function in Neoplasia

Descriptive Note:

Annual rept. 1 Oct 2001-30 Sep 2002

Corporate Author:

JOHNS HOPKINS UNIV BALTIMORE MD SCHOOLOF MEDICINE

Personal Author(s):

Report Date:

2002-10-01

Pagination or Media Count:

53.0

Abstract:

The overall goal of this project is to determine the regulatory mechanisms that activate fatty acid FA synthetic metabolism during malignant progression of prostate cancer, and to evaluate FA synthesis as a therapeutic target. The biosynthetic enzyme, fatty acid synthase FAS, is expressed at elevated levels in PCa cells and is a marker of tumors with activated FA synthesis. While PAS expression is androgen responsive, it persists or is reactivated in tumors after androgen ablation, and is high in 83 of lethal tumors examined at autopsy. Experimental model systems of PCa in vitro and in vivo show similar patterns of PAS activation, with increased PAS during progression to androgen independence. Tumor cell changes in fatty acid metabolism are insensitive to nutritional regulation, and tumor cells produce predominantly membrane lipids. Our experiments have led to the observation that growth factor signals mediated by activated kinases in PCa cells and transformation models activate the fatty acid synthesis pathway via modulation of SREBP-lc transcription factor levels, resulting in the tumor phenotype of activated PA metabolism that is insensitive to nutritional regulation. Small molecules that inhibit PAS are cytotoxic to tumors, and the mechanism of tumor cell killing is under investigation.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE