High Prevalence of Fatty Acid Synthase Expression in Colorectal Cancers in Middle Eastern Patients and Its Potential Role as a Therapeutic Target

Abstract

Many human epithelial cancers, particularly those with a poor prognosis, express high levels of fatty acid synthase (FASN), a key metabolic enzyme linked to synthesis of membrane phospholipids in cancer cells. Overexpression of FASN is linked with activation of the phosphatidylinositol-3'-kinase (PI3 K)/AKT pathway. However, the role of FASN in colorectal cancer (CRC) has not been fully elucidated. We investigated the expression of FASN and determined its functional association with the PI3/AKT pathway in CRC. Expression of FASN and its associated targets were studied by immunohistochemistry on 448 CRC tumors in a tissue microarray (TMA) format. Analysis of apoptosis and cell cycle was evaluated in vitro using CRC cell lines by flow cytometry and DNA fragmentation assays. Protein expression was determined by immunohistochemistry and western blotting. In vivo xenograft studies were performed using CRC cell lines and NUDE mice. Correlation of FASN with various clinicopathological parameters on 448 CRC samples was assessed. Activated AKT was found in 294/409 (71.9%) of CRC and was associated with FASN overexpression. FASN expression was observed in 27.1% (109/403) of Middle Eastern CRC. Additionally, FASN expression was significantly more common in tumors characterized by microsatellite instability (MSI) than in those characterized by microsatellite stability (MSS) (P<0.01). Our in vitro data using HCT-15, an MSI CRC cell line, showed a better apoptotic response after inhibition of FASN activity as compared with Colo-320, an MSS CRC cell line. Finally, treatment of HCT-15 cell line xenografts with C-75 resulted in growth inhibition of tumors in NUDE mice via downregulation of FASN and AKT activity. These data identify FASN as a potential biomarker and a novel therapeutic target in distinct molecular subtypes of CRC.