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 ( FABP5 ) in colorectal cancer (CRC). We observed marked down-regulation of FABP5 in CRC. Data from functional assays revealed inhibitory effects of FABP5 on cell proliferation, colony formation, migration, invasion as well as tumor growth in vivo . In terms of mechanistic insights, FABP5 interacted with fatty acid synthase ( FASN ) and activated the ubiquitin proteasome pathway, leading to a decrease in FASN expression and lipid accumulation, moreover, suppressing mTOR signaling and facilitating cell autophagy. Orlistat, a FASN inhibitor, exerted anti-cancer effects both in vivo and in vitro . Furthermore, the upstream RNA demethylase ALKBH5 positively regulated FABP5 expression via an m 6 A-independent mechanism. Overall, our collective findings offer valuable insights into the critical role of the ALKBH5 / FABP5 / FASN/mTOR axis in tumor progression and uncover a potential mechanism linking lipid metabolism to development of CRC, providing novel therapeutic targets for future interventions.

Global research trends and prospects of cellular metabolism in colorectal cancer

“…The antitumor activity of FASN attaches great significance in its prospect of being a promising therapeutic strategy for CRC. Intriguingly, Ye et al [ 40 ] recently found that fatty acid-binding protein 5 degrades FASN; however, this process ultimately promotes lipid accumulation and inhibits mTOR signaling, which facilitates cell autophagy. Taken together, lipid metabolism, especially fatty acid metabolism, plays a fundamental role in CRC growth, metastasis and chemoresistance.…”

Modification patterns and metabolic characteristics of m6A regulators in digestive tract tumors

“…The possible reason for this is that we based our analysis on mRNA levels, while other factors such as post-transcriptional mechanisms may also influence the effect of ALKBH5 on COAD prognosis. The role of ALKBH5 in COAD reported in the literature is also controversial [ [26] , [27] , [28] ]. Therefore, further experimental studies are required to confirm it.…”

Elucidating prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma: a novel anoikis-related gene signature model

“…Additionally, the ABL1 gene regulates cytoskeletal dynamics and is linked to tumor drug resistance and cell migration ( 36 , 37 ). FASN encodes a fatty acid synthase that catalyzes the conversion of acetyl coenzyme A and malonyl coenzyme A to palmitate ( 38 ). Overexpression and hyperactivity of FASN are typically associated with malignant cells.…”