Fatty Acid Synthase Inhibitor Cytotoxicity: Depletion of the Coenzyme-A Pool
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2003
- Accession Number
- ADA415316
Entities
People
- Francis P. Kuhajda
Organizations
- Johns Hopkins University