IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer
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...
Main Authors: | , , , , , , , , , , , |
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Format: | Article |
Language: | English |
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Hindawi Limited
2020-01-01
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Series: | Oxidative Medicine and Cellular Longevity |
Online Access: | http://dx.doi.org/10.1155/2020/1675613 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lei Zhang Wen Liu Fangyan Liu Qun Wang Mengjiao Song Qi Yu Kun Tang Tieshan Teng Dongdong Wu Xijing Wang Wuqi Han Yanzhang Li |
spellingShingle |
Lei Zhang Wen Liu Fangyan Liu Qun Wang Mengjiao Song Qi Yu Kun Tang Tieshan Teng Dongdong Wu Xijing Wang Wuqi Han Yanzhang Li IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer Oxidative Medicine and Cellular Longevity |
author_facet |
Lei Zhang Wen Liu Fangyan Liu Qun Wang Mengjiao Song Qi Yu Kun Tang Tieshan Teng Dongdong Wu Xijing Wang Wuqi Han Yanzhang Li |
author_sort |
Lei Zhang |
title |
IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer |
title_short |
IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer |
title_full |
IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer |
title_fullStr |
IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer |
title_full_unstemmed |
IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer |
title_sort |
imca induces ferroptosis mediated by slc7a11 through the ampk/mtor pathway in colorectal cancer |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2020-01-01 |
description |
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. |
url |
http://dx.doi.org/10.1155/2020/1675613 |
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doaj-d26945723d5e4da4b0f2463c9b3afdb22020-11-25T02:04:12ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942020-01-01202010.1155/2020/16756131675613IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal CancerLei Zhang0Wen Liu1Fangyan Liu2Qun Wang3Mengjiao Song4Qi Yu5Kun Tang6Tieshan Teng7Dongdong Wu8Xijing Wang9Wuqi Han10Yanzhang Li11Cell 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, ChinaCell 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, ChinaCell 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, ChinaCell 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, ChinaCell 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, ChinaCell 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, ChinaCell 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, ChinaCell 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, ChinaCell 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, ChinaDepartment of Dermatology, Second People’s Hospital of Zhengzhou, Zhengzhou 450006, ChinaKaifeng Food and Drug Inspection Institute, Kaifeng 475004, ChinaCell 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, ChinaFerroptosis, 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.http://dx.doi.org/10.1155/2020/1675613 |