Accession Number:

ADA415316

Title:

Fatty Acid Synthase Inhibitor Cytotoxicity: Depletion of the Coenzyme-A Pool

Descriptive Note:

Annual rept. 1 Apr 2002-31 Mar 2003

Corporate Author:

JOHNS HOPKINS UNIV BALTIMORE MD SCHOOLOF MEDICINE

Personal Author(s):

Report Date:

2003-04-01

Pagination or Media Count:

7.0

Abstract:

Inhibition of fatty acid synthase FAS in human cancer cells leads to cytotoxicity without evidence of DNA damage. Based on this and other biochemical observations, attention was focused on the cytoplasm as the site for the origin of C75 cytotoxicity to human cancer cells. In light of recent data that showed a marked increase in malonyl-CoA following FAS inhibition, this grant was focused on coenzyme-A depletion as a key mechanism of action leading to cytotoxicity. While pursuing this line of investigation with exhaustive metabolic labeling studies with 14Cpantothenate during the first 6 months, it became clear that FAS inhibition did not lead to depletion of coenzyme-A. However, it became clear that following FAS inhibition, cancer cells rapidly reduced protein synthesis. This global reduction in protein synthesis closely approximated the endoplasmic reticulum ER or unfolded-protein stress response that occurs during apoptosis. Thus, while the focus of the grant remains on studying cytoplasmic events that lead to cancer cell cytotoxicity of FAS inhibition, we have shifted our emphasis from the CoA depletion hypothesis to the ER stress response. We have shown that eukaryotic initiation factor 2 alpha EIF2a, a key regulator of protein synthesis and the ER stress response, is involved in the cytotoxic mechanism of C75 against human breast cancer cells.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE