Abstract 5289: HO-3867 inhibits cell migration, invasion and tumor growth of ovarian cancer through alterations in fatty acid synthase (FASN) and focal adhesion kinase (FAK) signaling

Abstract

Abstract Fatty acid synthase (FAS) has been found to be overexpressed in a wide range of epithelial tumors, including ovarian cancer. Expression of FAS, the key enzyme in de novo synthesis of long-chain fatty acids, is normally low but increases in cancer. The increase of FAS levels regulates cell proliferation, apoptosis and migration in tumors. In tumor cells, the inhibition of FAS elicits cell cycle arrest and apoptosis, so it is considered a potential drug target for cancer therapy. A2780 and SKOV3 ovarian cancer cells were grown in vitro and exposed to culture media containing 10 μM of HO-3867 for a period of 12 or 24 hours. FAS protein level analysis and examination of proliferation and migration genes was performed by Western blotting. RT-PCR was used to examine mRNA levels. FAS activity levels were measured by spectrophotometry. FAS, Cyclin D1 and VEGF expression levels were analyzed in vivo using both Western blotting, RT-PCR and immunohistochemistry. We found that HO-3867 significantly inhibits the FAS activity levels in A2780 and SKOV3 ovarian cancer cells. FAS mRNA levels were significantly decreased in HO-3867-treated cells. Based upon these results, we investigated how HO-3867 inhibits FAS expression and activity in ovarian cancer cells. We found that FAS-regulating genes such as SREBP1 & 2 and pHER1 were clearly inhibited by HO-3867 exposure. Collectively, our results indicate that HO-3867 inhibition of FAS leads to inhibition of the cell migration genes FAK, ERK1/2, c-Myc, upregulation of the proliferation-regulating genes p21, p27 and downregulation of cyclin D1, resulting in inhibition of ovarian cancer cell proliferation, migration and tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5289.