SignificanceStandard of care for metastatic castration-resistant prostate cancer (mCRPC) mainly relies on suppression of androgen receptor (AR) signaling. This approach has no lasting benefit due to the emergence of resistance mechanisms, such as ligand-independent splicing variant AR-V7. A metabolic feature of mCRPC is the upregulation of de novo lipogenesis to provide substrates and fuel for metastatic spread. Whether increased levels of fats affect AR signaling to promote an aggressive disease remains to be determined. Using a selective and potent inhibitor of fatty acid synthase we demonstrate that suppression of this key enzyme inhibits AR, most importantly AR-V7, and reduces mCRPC growth. Our findings offer a therapeutic opportunity for mCRPC and a potential mechanism to overcome resistance to AR inhibitors.

Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma. ' 2008 Wiley-Liss, Inc.Key words: melanoma; fatty acid synthase; metastasis; Orlistat; B16-F10 cells Endogenous fatty acid synthesis from the small carbon precursors acetyl-CoA and malonyl-CoA is dependent on the activity of fatty acid synthase (FASN, EC2.3.1.85). In most of the cells, FASN is downregulated by the dietary fatty acids, with exception of lipogenic tissues as liver, lactating breast, fetal lung and adipose tissue.1,2 Recent studies provide compelling evidence that neoplastic lipogenesis is essential for cancer cell survival. In fact, several human epithelial malignancies, such as those of prostate, breast, ovary, bladder, lung, stomach and oral cavity, melanoma as well as soft tissue sarcomas overexpress FASN. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] For some of these tumors, such as prostate, breast and ovarian cancers and melanoma, 4,5,9,12 FASN overexpression has also been associated with a poor prognosis. Experimental studies have shown that FASN inhibition reduces cell proliferation by blocking DNA replication during S-phase, induces apoptosis, [17][18][19][20] and decrease the size of prostate, ovarian and breast cancer xenografts. 3,21,22 In addition, the inhibition of FASN activity has a chemopreventive effect in the breast cancer transgenic neu-N mouse model. 23 Orlistat (tetrahydrolipstatin) is an irreversible inhibitor of pancreatic and gastric lipases clinically used because of its antiobesity properties that also blocks the activity of the thioesterase domain of FASN. 24 In fact, FASN inhibition by Orlistat reduces proliferation and promotes apoptosis in prostate, breast and stomach cancer cel...

Fatty acid synthase (FASN) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids. It is downregulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, including head and neck squamous cell carcinomas (HNSCC), overexpress FASN, which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein. Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively. To explore whether the inhibition of FASN could impact oral tongue squamous cell carcinoma (OTSCC) metastatic spread, an orthotopic model was developed by the implantation of SCC-9 ZsGreen LN-1 cells into the tongue of BALB/c nude mice. These cells were isolated through in vivo selection, show a more invasive behavior in vitro than the parental cells, and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only. SCC-9 ZsGreen LN-1 cells also exhibit enhanced production of MMP-2, ERBB2, and CDH2. The treatment with orlistat reduced proliferation and migration, promoted apoptosis, and stimulated the secretion of VEGFA 165b by SCC-9 ZsGreen LN-1 cells. In vivo, the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and, importantly, reduced the number of metastatic cervical lymph nodes by 43%. These results suggest that FASN is a potential molecular target for the chemotherapy of patients with OTSCC. Mol Cancer Ther; 13(3); 585-95. Ó2013 AACR.