A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction
- 1 February 2008
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 7 (2), 263-270
- https://doi.org/10.1158/1535-7163.mct-07-0445
Abstract
Multidrug resistance is a major problem in successful cancer chemotherapy. Various mechanisms of resistance, such as ABC transporter-mediated drug efflux, have been discovered using established model cancer cell lines. While characterizing a drug-resistant breast cancer cell line, MCF7/AdVp3000, we found that fatty acid synthase (FASN) is overexpressed. In this study, we showed that ectopic overexpression of FASN indeed causes drug resistance and that reducing the FASN expression increased the drug sensitivity in breast cancer cell lines MCF7 and MDA-MB-468 but not in the normal mammary epithelial cell line MCF10A1. Use of FASN inhibitor, Orlistat, at low concentrations also sensitized cells with FASN overexpression to anticancer drugs. The FASN-mediated drug resistance appears to be due to a decrease in drug-induced apoptosis from an overproduction of palmitic acid by FASN. Together with previous findings of FASN as a poor prognosis marker for breast cancer patients, our results suggest that FASN overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy. [Mol Cancer Ther 2008;7(2):263–70]Keywords
This publication has 21 references indexed in Scilit:
- Fatty Acid Synthase and Cancer: New Application of an Old PathwayCancer Research, 2006
- Acetyl-CoA Carboxylase α Is Essential to Breast Cancer Cell SurvivalCancer Research, 2006
- Sensitizing hormone-refractory prostate cancer cells to drug treatment by targeting 14-3-3σMolecular Cancer Therapeutics, 2006
- Identification of 14-3-3σ as a Contributor to Drug Resistance in Human Breast Cancer Cells Using Functional Proteomic AnalysisCancer Research, 2006
- Increased ratio of saturated to unsaturated C18 fatty acids in colonic adenocarcinoma: Implications for cryotherapy and lipid raft functionMedical Hypotheses, 2005
- Expression Profiling of ABC Transporters in a Drug-Resistant Breast Cancer Cell Line Using AmpArrayPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2005
- Targeting Fatty Acid Synthase: Potential for Therapeutic Intervention in Her-2/neu-Overexpressing Breast CancerDrug News & Perspectives, 2005
- Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growthOncogene, 2004
- Orlistat Is a Novel Inhibitor of Fatty Acid Synthase with Antitumor ActivityCancer Research, 2004
- Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cellsCell Death & Differentiation, 2001