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Int J Biol Sci 2023; 19(10):3115-3127. doi:10.7150/ijbs.85285 This issue Cite

Research Paper

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

Mujie Ye^*✉, Chunhua Hu^*, Tiaotiao Chen^*, Ping Yu^*, Jinhao Chen, Feiyu Lu, Lin Xu, Yuan Zhong, Lijun Yan, Jingbao Kan, Jianan Bai, Xiaolin Li, Ye Tian^✉, Qiyun Tang^✉

Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, Nanjing, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Qiyun Tang, Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, NO.300 Guangzhou Road, Nanjing, China. Email: tqy831com. Ye Tian, Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, NO.300 Guangzhou Road, Nanjing, China. Email: tianye6626com. Mujie Ye, Department of Geriatric Gastroenterology, Neuroendocrine Tumor Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Institute of Neuroendocrine Tumor, Nanjing Medical University, NO.300 Guangzhou Road, Nanjing, China. Email: mujiey0629com More

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 m⁶A-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.

Keywords: Colorectal cancer, Lipid metabolism, FABP5, FASN, Autophagy, N6-methyladenosine, Orlistat

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