IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Lei Zhang; Wen Liu; Fangyan Liu; Qun Wang; Mengjiao Song; Qi Yu; Kun Tang; Tieshan Teng; Dongdong Wu; Xijing Wang; Wuqi Han; Yanzhang Li

doi:10.1155/2020/1675613

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Oxid Med Cell Longev. 2020 Apr 3:2020:1675613. doi: 10.1155/2020/1675613. eCollection 2020.

Authors

Lei Zhang¹, Wen Liu¹, Fangyan Liu¹, Qun Wang¹, Mengjiao Song¹, Qi Yu¹, Kun Tang¹, Tieshan Teng¹, Dongdong Wu¹, Xijing Wang², Wuqi Han³, Yanzhang Li¹

Affiliations

¹ Cell Signal Transduction Laboratory, Bioinformatics Center, Laboratory for Nanomedicine, Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China.
² Department of Dermatology, Second People's Hospital of Zhengzhou, Zhengzhou 450006, China.
³ Kaifeng Food and Drug Inspection Institute, Kaifeng 475004, China.

Abstract

Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by iron-dependent lipid peroxidation after inactivation of the cystine/glutamate antiporter system xc^-, which is composed of solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2). Therefore, inducing ferroptosis through inhibiting the cystine/glutamate antiporter system xc^- may be an effective way to treat cancer. In previous screening tests, we found that the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) significantly inhibited the viability of colorectal cancer cells. However, the impact of IMCA on ferroptosis remains unknown. Hence, this study investigated the effect of IMCA on ferroptosis and elucidated the underlying molecular mechanism. Results showed that IMCA significantly inhibited the cell viability of colorectal cancer cells in vitro and inhibited tumor growth with negligible organ toxicity in vivo. Further studies showed that IMCA significantly induced the ferroptosis of colorectal cancer cells. Mechanistically, IMCA downregulated the expression of SLC7A11 and decreased the contents of cysteine and glutathione, which resulted in reactive oxygen species accumulation and ferroptosis. Furthermore, overexpression of SLC7A11 significantly attenuated the ferroptosis caused by IMCA. In addition, IMCA regulated the activity of the AMPK/mTOR/p70S6k signaling pathway, which is related to the activity of SLC7A11 and ferroptosis. Collectively, our research provided experimental evidences on the activity and mechanism of ferroptosis induced by IMCA and revealed that IMCA might be a promising therapeutic drug for colorectal cancer.