Promotion of colorectal cancer cell death by ezetimibe via mTOR signaling-dependent mitochondrial dysfunction

Yuanyuan Zheng; Wenjuan Yang; Yewei Jia; Jie Ji; Liwei Wu; Jiao Feng; Yan Li; Ziqi Cheng; Jie Zhang; Jingjing Li; Weiqi Dai; Xuanfu Xu; Jianye Wu; Yingqun Zhou; Chuanyong Guo

doi:10.3389/fphar.2023.1081980

Promotion of colorectal cancer cell death by ezetimibe via mTOR signaling-dependent mitochondrial dysfunction

Front Pharmacol. 2023 Feb 7:14:1081980. doi: 10.3389/fphar.2023.1081980. eCollection 2023.

Authors

Yuanyuan Zheng¹, Wenjuan Yang², Yewei Jia³, Jie Ji¹, Liwei Wu¹, Jiao Feng¹, Yan Li¹, Ziqi Cheng¹, Jie Zhang¹, Jingjing Li⁴, Weiqi Dai⁴, Xuanfu Xu⁴, Jianye Wu⁵, Yingqun Zhou¹, Chuanyong Guo¹

Affiliations

¹ Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
² Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine, Shanghai, China.
³ Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
⁴ Department of Gastroenterology, Shidong Hospital, Shanghai, China.
⁵ Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, China.

Abstract

Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide, with high morbidity and mortality rates. In recent years, high-fat diet has been shown to increase CRC morbidity, highlighting the possibility of the application of hypolipidemic drugs for CRC treatment. In this study, we preliminarily evaluated the effects and mechnisms of ezetimibe against CRC through the blockage of lipid absorption in small intesine. Methods: In this study, CRC cell proliferation, invasion, apoptosis, and autophagy were evaluated using cellular and molecular assays. Fluorescent microscopy, and a flow cytometric assay were used to assess mitochondrial activity in vitro. A subcutaneous xenograft mouse model was used to evaluate the effects of ezetimibe in vivo. Results: We found that ezetimibe inhibited CRC cell proliferation, and migration, and facilitated autophage-associated apoptosis in HCT116 and Caco2 cells. Ezetimibe-induced mitochondrial dysfunction in CRC cells was found to be correlated with mTOR signaling activity. Discussion: Ezetimibe exhibits effects against CRC through the promotion of cancer cell death via mTOR signaling-dependent mitochondrial dysfunction, highlighting its potential value in CRC therapy.

Keywords: MTOR signaling; cell death; colorectal cancer; ezetimibe; mitochondrial dysfunction.

Grants and funding

National Natural Science Foundation of China (No. 82100638, No. 82102956, No. 82002539), Yangfan Project of Shanghai Science and Technology Commission (No. 20YF1443300, No. 21YF1435400), China Postdoctoral Science Foundation (No. 2022M712412), Health System Innovation Project of Shanghai Putuo Science and Technology Commission (No. PTKWWS202303).