Document Detail


Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity.
MedLine Citation:
PMID:  11444828     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy.
Authors:
J N Thupari; M L Pinn; F P Kuhajda
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  285     ISSN:  0006-291X     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2001 Jul 
Date Detail:
Created Date:  2001-07-10     Completed Date:  2001-08-16     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  217-23     Citation Subset:  IM    
Copyright Information:
Copyright 2001 Academic Press.
Affiliation:
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetyl-CoA Carboxylase / antagonists & inhibitors
Antilipemic Agents / pharmacology
Apoptosis / drug effects,  physiology*
Breast Neoplasms
Carnitine O-Palmitoyltransferase / antagonists & inhibitors
Cell Survival / drug effects
Cerulenin / toxicity*
Enzyme Inhibitors / pharmacology
Epoxy Compounds / pharmacology
Fatty Acid Synthetase Complex / antagonists & inhibitors*
Fatty Acids / metabolism*
Female
Furans / pharmacology
Humans
Kinetics
Malonyl Coenzyme A / metabolism*,  toxicity
Models, Biological
Oxidation-Reduction
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
R01 CA87850-02/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antilipemic Agents; 0/Enzyme Inhibitors; 0/Epoxy Compounds; 0/Fatty Acids; 0/Furans; 17397-89-6/Cerulenin; 524-14-1/Malonyl Coenzyme A; 54857-86-2/5-(tetradecyloxy)-2-furancarboxylic acid; 82258-36-4/etomoxir; EC 2.3.1.21/Carnitine O-Palmitoyltransferase; EC 6.-/Fatty Acid Synthetase Complex; EC 6.4.1.2/Acetyl-CoA Carboxylase
Comments/Corrections
Erratum In:
Biochem Biophys Res Commun 2002 Jul 12;295(2):570

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