Abstract
Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has been shown to be deregulated in several cancers, including epithelial ovarian carcinoma (EOC). In this study, we investigated the function of the FASN signaling pathway in a large series of Middle Eastern EOC patient samples, a panel of cell lines and nude mouse model. Using immunohistochemistry, we detected overexpression of FASN in 75.5% (114/151) of the tumor samples. Overexpression of FASN was associated significantly with tumor proliferative marker Ki-67 (P = 0.0009), activated AKT (P = 0.0117) and XIAP (P = 0.0046). Treatment of EOC cell lines with C-75, a selective inhibitor of FASN, caused inhibition of EOC cell viability via induction of apoptosis. Inhibition of FASN by C-75 led apoptosis via the mitochondrial pathway. FASN inhibition caused downregulation of activated AKT and its downstream targets. In addition, inhibition by FASN siRNA caused downregulation of FASN and activation of caspases, suggesting the role of FASN in C-75 mediated apoptosis. Furthermore, treatment of EOC cells with subtoxic doses of C-75 augmented the effect of cisplatin-mediated induction of apoptosis. Finally, treatment of EOC cell line xenografts with a combination of C-75 and cisplatin resulted in growth inhibition of tumors in nude mice through downregulation of FASN and activation of caspases. Altogether, our results show overexpression of FASN in Middle Eastern EOC, suggesting that FASN may be a potential therapeutic target in a subset of EOC, alone or in combination with other conventional chemotherapeutic agents.
Highlights
Ovarian cancer is one of the lethal gynecologic malignancies and this is due in large part to the resistance of recurrent ovarian cancer cells to standard chemotherapeutic strategies [1]
Since FOXO1 transcription factors have been reported to be a downstream target of AKT and are known to promote transcription of genes involved in cell cycle arrest and apoptosis [30], we investigated the level of FOXO1 phosphorylation in C-75 treated and untreated epithelial ovarian carcinoma (EOC) cells by Western blotting
We have aimed to clarify this issue by investigating the effect of Fatty acid synthase (FASN) inhibition on cell growth, proliferation and FASN/PI3K/AKT signal transduction in a panel of EOC cell lines
Summary
Ovarian cancer is one of the lethal gynecologic malignancies and this is due in large part to the resistance of recurrent ovarian cancer cells to standard chemotherapeutic strategies [1]. Of the different chemotherapeutic agents in use for treating cancer, platinum-based chemotherapy is often used to treat recurrent ovarian cancers, but many of the ovarian cancer cells are resistant to the platinum-based agents [2]. This resistance to chemotherapy results in recurrence and the loss of life. FASN expression levels are relatively low, since fatty acid is generally supplied by dietary fatty acid. Upregulation of FASN expression in cancer cells has been linked to phosphatidylinositol-3-kinase (PI3K)/ AKT signaling pathway [17,18,19]. PI3K pathway has been shown to be capable of negatively regulating FASNinduced cell death [19]
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