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FABP5 suppresses colorectal cancer progression via mTOR-mediated autophagy by decreasing FASN expression
Mujie Ye1, Chunhua Hu1, Tiaotiao Chen1
1Department 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.
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.
Insights
Fatty acid-binding protein 5 (FABP5) suppresses colorectal cancer (CRC) progression by inhibiting proliferation and tumor growth. Its downregulation in CRC suggests FABP5 as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lipid metabolism is crucial in cancer development, particularly in digestive system tumors like colorectal cancer (CRC).
- Fatty acid-binding protein 5 (FABP5) role in CRC remains to be fully elucidated.
Purpose of the Study:
- Investigate the function of FABP5 in colorectal cancer (CRC).
- Elucidate the underlying molecular mechanisms of FABP5's action in CRC.
- Identify potential therapeutic targets for CRC intervention.
Main Methods:
- Gene expression analysis in CRC tissues.
- In vitro functional assays (proliferation, colony formation, migration, invasion).
- In vivo tumor growth studies.
- Mechanistic studies involving protein-protein interactions, ubiquitination assays, and signaling pathway analysis.
- Pharmacological inhibition of FASN.
Main Results:
- FABP5 was significantly downregulated in CRC.
- FABP5 exhibited inhibitory effects on CRC cell proliferation, colony formation, migration, invasion, and tumor growth.
- FABP5 interacted with FASN, promoting its degradation via the ubiquitin-proteasome pathway, reducing lipid accumulation, suppressing mTOR signaling, and enhancing autophagy.
- Orlistat (FASN inhibitor) demonstrated anti-cancer effects.
- ALKBH5 positively regulated FABP5 expression through an m6A-independent mechanism.
Conclusions:
- FABP5 acts as a tumor suppressor in CRC.
- The ALKBH5/FABP5/FASN/mTOR axis is critical in CRC progression.
- Targeting this axis offers potential therapeutic strategies for CRC.
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