Blockade of Fatty Acid Synthase Triggers Significant Apoptosis in Mantle Cell Lymphoma

Wayne State University, United States of America
PLoS ONE (Impact Factor: 3.23). 04/2012; 7(4):e33738. DOI: 10.1371/journal.pone.0033738
Source: PubMed


Fatty acid synthase (FASN), a key player in the de novo synthetic pathway of long-chain fatty acids, has been shown to contribute to the tumorigenesis in various types of solid tumors. We here report that FASN is highly and consistently expressed in mantle cell lymphoma (MCL), an aggressive form of B-cell lymphoid malignancy. Specifically, the expression of FASN was detectable in all four MCL cell lines and 15 tumors examined. In contrast, benign lymphoid tissues and peripheral blood mononuclear cells from normal donors were negative. Treatment of MCL cell lines with orlistat, a FASN inhibitor, resulted in significant apoptosis. Knockdown of FASN expression using siRNA, which also significantly decreased the growth of MCL cells, led to a dramatic decrease in the cyclin D1 level. β-catenin, which has been previously reported to be upregulated in a subset of MCL tumors, contributed to the high level of FASN in MCL cells, Interesting, siRNA knock-down of FASN in turn down-regulated β-catenin. In conclusion, our data supports the concept that FASN contributes to the pathogenesis of MCL, by collaborating with β-catenin. In view of its high and consistent expression in MCL, FASN inhibitors may hold promises for treating MCL.

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Available from: Andrew R Belch, Oct 06, 2014
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    • "Menendez et al. 2005 (9) In vitro treatment (human breast cancer cell line) 0 to 20 µM of orlistat for 72 hours Orlistat can be considered as a novel therapeutic drug for treating Her2/neu over-expressing breast carcinomas and inhibiting FASN activity. Garcia et al. 2006 (11) In vivo treatment (Male Wistar rats) 200 mg/kg of chow for 30 days Orlistat significantly increased the number of colonic aberrant crypt foci (ACF) and cell proliferation Gelebart et al. 2012 (12) In vitro treatment (mantle cell lymphoma cell line) 0 to 20 µM of orlistat for 48 hours The expression of FASN was detectable and high in mantle cell lymphoma (MCL) and was negative in normal cells. "
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    ABSTRACT: Background: Orlistat (Xenical) is an approved medication for treating obesity. Recent studies suggested a new application for orlistat as an antitumor agent. Objectives: The aim of this review was to describe the effect of orlistat as an antitumor agent on growth of cancer cells. Patients and Methods: Articles were identified in data-bases such as Google Scholar, PubMed, Scopus and Proquest. Forty-nine articles were found with key words such as orlistat and obesity, orlistat and neoplasm, orlistat and proliferation, antitumor and orlistat, and fatty acid synthase and orlistat. Finally 25 articles were selected that were published from 2005 until the present and investigated orlistat functions on cancer progression. Results: Orlistat reduced cancer cells growth in vitro and in vivo. Orlistat inhibited approximately 50% of proliferation and decreased tumor size compared with control groups. It seems that, antitumor effects of orlistat are dose dependent and its high concentrations inhibit proliferation of cells more than low concentrations. Conclusions: Orlistat inhibited fatty acid synthase, decreased tumor cells proliferation, stimulated tumor cell apoptosis and decreased viability. Thus it can act as an anti-tumor drug. By changing the formulation of oral orlistat, we can produce a novel drug with more bioavailability for absorption from the gastrointestinal tract and more anti-tumor activity.
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    • "In addition to cancer cells, high expression of FASN has been reported in lipogenic tissue, such as the liver [28]. The abundant expression of FASN and its function on de novo fatty acid synthesis in cancer cells is accompanied by carcinogenesis and is relevance to unsatisfactory prognosis [29]. Several studies have demonstrated that suppression of FASN activity promotes apoptosis in cancer cells. "
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    ABSTRACT: The inhibition of the mammalian de novo synthesis of long-chain saturated fatty acids (LCFAs) by blocking the fatty acid synthase (FASN) enzyme activity in tumor cells that overexpress FASN can promote apoptosis, without apparent cytotoxic to non-tumor cells. The present study aimed to focus on the potent inhibitory effect of capsaicin on the fatty acid synthesis pathway inducing apoptosis of capsaicin in HepG2 cells. The use of capsaicin as a source for a new FASN inhibitor will provide new insight into its possible application as a selective anti-cancer therapy. The present findings showed that capsaicin promoted apoptosis as well as cell cycle arrest in the G0/G1 phase. The onset of apoptosis was correlated with a dissipation of mitochondrial membrane potential (ΔΨm). Apoptotic induction by capsaicin was mediated by inhibition of FASN protein expression which was accompanied by decreasing its activity on the de novo fatty acid synthesis. The expression of FASN was higher in HepG2 cells than in normal hepatocytes that were resistant to undergoing apoptosis following capsaicin administration. Moreover, the inhibitory effect of capsaicin on FASN expression and activity was found to be mediated by an increase of intracellular reactive oxygen species (ROS) generation. Treatment of HepG2 cells with capsaicin failed to alter ACC and ACLY protein expression, suggesting ACC and ACLY might not be the specific targets of capsaicin to induce apoptosis. An accumulation of malonyl-CoA level following FASN inhibition represented a major cause of mitochondrial-dependent apoptotic induction instead of deprivation of fatty acid per se. Here, we also obtained similar results with C75 that exhibited apoptosis induction by reducing the levels of fatty acid without any change in the abundance of FASN expression along with increasing ROS production. Collectively, our results provide novel evidence that capsaicin exhibits a potent anti-cancer property by targeting FASN protein in HepG2 cells.
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    • "Since adipocytes may be providing cancer cells with FFA as a fuel source, inhibition of lipolysis, and FFA efflux from adipocytes or blocking of cancer cell FFA oxidation could represent therapeutic targets. Inhibition of FFA oxidation, such as with etomoxir, has been shown to impair a variety of hematological malignancies, including myeloma cell (83), AML (84), CLL (85), and mantle cell lymphoma (86). Since cancer cells, such as ovarian cancer, increase their FFA oxidation rate when co-cultured with adipocytes (40), targeting this pathway may be particularly beneficial in obese patients. "
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