A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction.
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.
Liu
Hailan
H
Department of Pharmacology and Toxicology, Walther Oncology Center/Walther Cancer Institute and Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Liu
Yang
Y
Zhang
Jian-Ting
JT
D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019308:Palmitic Acid / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D019308:Palmitic Acid; D064429:Fatty Acid Synthases