Patuletin induces apoptosis of human breast cancer SK‑BR‑3 cell line via inhibiting fatty acid synthase gene expression and activity

Abstract

Abstract. Fatty acid synthase (FASN) is a key enzyme involved in fatty acid biosynthesis and serves an important role in breast cancer development. The aim of the present study was to investigate the effects of patuletin on the gene expression and activity of FASN in the human breast cancer SK-BR-3 cell line, and the apoptotic effects of patuletin to breast cancer cells. Quantitative reverse transcription polymerase chain reaction, western blotting and intracellular FASN activity assays were used to evaluate FASN gene expression, protein expression and activity in patuletin-treated SK-BR-3 cells. MTT assays and flow cytometry were used to measure cell growth and cell apoptosis, respectively, following patuletin treatment. As a result, it was demonstrated that patuletin dose-dependently reduces FASN expression and intracellular activity in human breast cancer cells, and induces apoptosis in FASN over-expressing SK-BR-3 cells. Notably, apoptosis is associated with the reduction of intracellular FASN activity. The present study demonstrates that patuletin may be considered as a novel natural inhibitor of FASN, may induce anti-proliferative and pro-apoptotic effects in certain human breast cancer cells and may be useful for preventing and/or treating human breast cancer. IntroductionFatty acid synthase (FASN) is a multi-enzyme that catalyzes the de novo synthesis of palmitate (C16:0, a long-chain saturated fatty acid) from acetyl-CoA and malonyl-CoA, in the presence of NADPH (1). FASN is not only a key factor in the role of fatty acid biosynthesis for energy storage (2,3), but also its expression level increases significantly in adipose tissues and a variety of human carcinomas, including liver, breast, prostate, lung, endometrium, ovary, colon and pancreatic cancer (4-13). This prominent difference of FASN expression between normal and neoplastic tissues makes FASN a potential diagnostic tumor marker (14).Breast cancer is the most common type of cancer and a leading cause of cancer-associated mortalities among females, with a common feature of abnormal cell apoptosis in its development (15). In addition, high levels of FASN expression has been demonstrated to be associated with poor clinical outcome in breast carcinomas, suggesting that FASN expression and tumor aggressiveness are closely associated (4,16). It was identified that obesity may serve a crucial role in the incidence and progression of breast cancer (17). According to the close association between FASN, obesity and breast cancer, the studies of FASN inhibitors have indicated their role as targets for chemotherapy in breast cancer and a novel strategy for antineoplastic intervention (18). In fact, previous studies demonstrated that certain synthetic and natural FASN inhibitors, including C75, desoxyrhaponticin, rhaponticin and α-mangostin may lead to selective cytotoxicity in FASN over-expressing cancer cell lines (18)(19)(20). This result suggested again that the pharmacological inhibition of FASN may represent a potential target for drug development.In...

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