Abstract 1151: Overexpression of Fatty Acid Synthase is associated with inhibition of autophagy under conditions of metabolic stress in colorectal cancer cells

Abstract

Abstract Fatty Acid Synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly up regulated in colorectal cancer (CRC) and its activity is associated with poor prognosis. Recent studies suggest that FASN plays a crucial role in the survival of cancer cells by reprogramming metabolic pathways to maintain energy homeostasis under conditions of metabolic stress. However, the mechanisms of metabolic adaptation of cancer cells regulated by FASN to promote their survival are not yet fully understood. Cancer cells use autophagy as one of the survival strategies under metabolic stress. The purpose of our study was to determine the role of aberrant activation of FASN in regulation of autophagy in vitro and in human CRC. METHODS. Expression of p62 and LC3 (autophagy markers), pAMPK, and Cyclin D was assessed in CRC cell lines with altered expression of FASN cultured in normal, serum free medium and/or detached conditions by Western blot and confocal microscopy. Human specimens, including matching cancer, normal colon and liver metastasis tissues from 19 patients were analyzed for expression of FASN, p62, and pAMPK by immunohistochemistry (IHC). RESULTS. We demonstrated that under metabolic stress conditions overexpression of FASN is associated with a decrease in autophagy as shown by accumulation of p62, a marker of inhibition of autophagy, and a decrease in LC3A, an autophagosome marker, in CRC cell lines. Under energy stress conditions, overexpression of FASN is also associated with an increase in Cyclin D and a decrease in activation of pAMPK. Statistical analysis of IHC staining showed that expression of FASN, p62, and pAMPK is significantly higher in cancer and metastatic tissues as compared to normal colon tissues. Using Spearman's rank correlation, we determined moderate correlation between expression of FASN and p62 in human primary CRC and liver metastasis. Similar results were obtained using Western blot analysis on human normal colon and matching cancer tissues. CONCLUSIONS. Our data suggest that overexpression of FASN is protective during metabolic stress conditions by shifting metabolism towards higher energy production as indicated by activity of pAMPK. Furthermore, we have identified a novel link between FASN and p62, and showed that, under metabolic stress conditions, overexpression of FASN is associated with inhibition of autophagy. However, further studies are require to understand how FASN-mediated up regulation of p62 contributes to tumorigenesis. The differential expression of FASN in normal versus cancer cells makes de novo lipogenesis a desirable target for therapeutic intervention. Understanding the role of FASN in regulation of survival and aggressive behavior of cancer cells will uncover new therapeutic approaches in CRC. Citation Format: Yekaterina Y. Zaytseva, Jennifer W. Harris, Ji Tae Kim, Tianyan Gao, Eun Y. Lee, Heidi L. Weiss, B Mark Evers. Overexpression of Fatty Acid Synthase is associated with inhibition of autophagy under conditions of metabolic stress in colorectal cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2015-1151