Acquired and intrinsic radioresistance remains a major challenge during the treatment of patients with colorectal cancer (CRC). Aberrant cholesterol metabolism precipitates the development of multiple cancers. Here, we report that exogenous or endogenous cholesterol enhances the radioresistance of CRC cells. The addition of cholesterol protects CRC cells against irradiation both in vitro and in vivo. Sterol response element-binding protein 1/fatty acid synthase (SREBP1/FASN) signaling is rapidly increased in response to radiation stimuli, resulting in cholesterol accumulation, cell proliferation and inhibition of apoptosis. Blocking the SREBP1/FASN pathway impedes cholesterol synthesis and accelerates radiation-induced CRC cell death. Our findings provide novel insights into the role of the SREBP1/FASN/cholesterol axis in radiotherapy and suggest that it may be a potential target for CRC treatment. Clinically, our results suggest that CRC patients undergoing radiotherapy may benefit from a lowered cholesterol intake.
Keywords: SREBP1/FASN signaling; cholesterol; colorectal cancer; radioresistance.
© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.