Abstract 1467: The potential role ofde novolipogenesis in the regulation of cell motility and invasion in colorectal cancer

The signaling networks that determine progression of cancer to a more aggressive metastatic phenotype include multiple alterations in the oncogenic pathways as well as significant changes in cellular metabolism. ATP-citrate lyase (ACLY) and Fatty Acid Synthase (FASN), key enzymes of lipid biogenesis, are significantly up-regulated and activated in many cancers and their activity is associated with poor prognosis, higher risk of disease recurrence, and death. Even though the role of neoplastic lipogenesis in providing proliferative and survival advantages to cancer cells has been defined, the impact of aberrant activation of lipogenic enzymes on the progression of cancer and development of metastases remains unknown. The purpose of the present study was to determine (i) the expression and/or activity of lipogenic enzymes in human colorectal cancer (CRC) tissues and cells, and (ii) the effect of their inhibition on signaling pathways involved in the regulation of migration and invasion. METHODS: Expression of FASN was analyzed in primary CRCs, matched liver metastasis and normal mucosa using Accumax Tissue Array. Expression of FASN and ACLY was also determined in CRC cell lines by Western blot. KM20, HT29, and HCT116 CRC cells with stable knockdown of ACLY and FASN were established, and downstream signaling pathways were analyzed (Western blot). Effect of inhibition of FASN on cell morphology (immunofluorescence microscopy), invasion (Boyden Chamber Assay), and endothelial cell adhesion was assessed. RESULTS: Expression of FASN was significantly higher in primary tumor and in liver metastases as compared to normal colon mucosa. FASN and ACLY were also highly expressed in CRC cell lines. Inhibition of lipogenic enzymes decreased migration and invasion of CRC cells. Mechanisms underlying these effects included disruption of CD44/c-MET signaling and decreased expression of pAkt, pFAK, RhoA, and RAC1. Furthermore, inhibition of FASN decreased the adherence of CRC cells to HMVEC-L endothelial cells.CONCLUSIONS: Increased expression of FASN and ACLY in both non-invasive and metastatic cell lines and CRC tissues suggest the potential role of de novo lipogenesis in the progression of CRC. Supporting this hypothesis, the current study demonstrates, for the first time, that inhibition of lipogenesis disrupts CD44/c-MET signaling which is well known to promote metastasis in several cancers including CRC. Furthermore, decreased expression of RhoA, Rac1, and pFAK, accompanied by changes in the actin cytoskeleton and the finding that inhibition of FASN attenuates the interaction of cancer cells with endothelial cells, suggests that activation of lipogenic enzymes plays a role in regulation of cancer cell motility and formation of metastasis. Together, these findings suggest that de novo lipogenesis may be a potential therapeutic target for early and advanced stages of CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1467. doi:10.1158/1538-7445.AM2011-1467