FABP5 suppresses colorectal cancer progression via mTOR-mediated autophagy by decreasing FASN expression

Abstract

Lipid metabolism plays an important role in the occurrence and development of cancer, in particular, digestive system tumors such as colon cancer. Here, we investigated the role of the fatty acid-binding protein 5 (<i>FABP5</i>) in colorectal cancer (CRC). We observed marked down-regulation of <i>FABP5</i> in CRC. Data from functional assays revealed inhibitory effects of <i>FABP5</i> on cell proliferation, colony formation, migration, invasion as well as tumor growth <i>in vivo</i>. In terms of mechanistic insights, <i>FABP5</i> interacted with fatty acid synthase (<i>FASN</i>) and activated the ubiquitin proteasome pathway, leading to a decrease in <i>FASN</i> expression and lipid accumulation, moreover, suppressing <i>mTOR</i> signaling and facilitating cell autophagy. Orlistat, a <i>FASN</i> inhibitor, exerted anti-cancer effects both <i>in vivo</i> and <i>in vitro</i>. Furthermore, the upstream RNA demethylase <i>ALKBH5</i> positively regulated <i>FABP5</i> expression via an m⁶A-independent mechanism. Overall, our collective findings offer valuable insights into the critical role of the <i>ALKBH5</i>/<i>FABP5</i>/<i>FASN/mTOR</i> axis in tumor progression and uncover a potential mechanism linking lipid metabolism to development of CRC, providing novel therapeutic targets for future interventions.