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HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation

Ferroptosis, a novel form of regulated cell death characterized by disrupted iron metabolism and the accumulation of lipid peroxides, has exhibited enormous potential in the therapy of cancer particularly clear cell renal cell carcinoma (ccRCC). Luteolin (Lut), a natural flavonoid widely existing in...

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Autores principales: Han, Shangting, Lin, Fangyou, Qi, Yucheng, Liu, Cong, Zhou, Linxiang, Xia, Yuqi, Chen, Kang, Xing, Ji, Liu, Zilin, Yu, Weimin, Zhang, Yunlong, Zhou, Xiangjun, Rao, Ting, Cheng, Fan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153929/
https://www.ncbi.nlm.nih.gov/pubmed/35656025
http://dx.doi.org/10.1155/2022/3846217
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author Han, Shangting
Lin, Fangyou
Qi, Yucheng
Liu, Cong
Zhou, Linxiang
Xia, Yuqi
Chen, Kang
Xing, Ji
Liu, Zilin
Yu, Weimin
Zhang, Yunlong
Zhou, Xiangjun
Rao, Ting
Cheng, Fan
author_facet Han, Shangting
Lin, Fangyou
Qi, Yucheng
Liu, Cong
Zhou, Linxiang
Xia, Yuqi
Chen, Kang
Xing, Ji
Liu, Zilin
Yu, Weimin
Zhang, Yunlong
Zhou, Xiangjun
Rao, Ting
Cheng, Fan
author_sort Han, Shangting
collection PubMed
description Ferroptosis, a novel form of regulated cell death characterized by disrupted iron metabolism and the accumulation of lipid peroxides, has exhibited enormous potential in the therapy of cancer particularly clear cell renal cell carcinoma (ccRCC). Luteolin (Lut), a natural flavonoid widely existing in various fruits and vegetables, has been proven to exert potent anticancer activity in vitro and in vivo. However, previous studies on the anticancer mechanism of Lut have been shown in apoptosis but not ferroptosis. In the present study, we identified that Lut substantially inhibited the survival of ccRCC in vitro and in vivo, and this phenomenon was accompanied by excessively increased intracellular Fe(2+) and abnormal depletion of GSH. In addition, Lut induced the imbalance of mitochondrial membrane potential, classical morphological alterations of mitochondrial ferroptosis, generation of ROS, and occurrence of lipid peroxidation in an iron-dependent manner in ccRCC cells. However, these alterations induced by Lut could be reversed to some extent by the iron ion chelator deferiprone or the ferroptosis inhibitor ferrostatin-1, indicating that ccRCC cells treated with Lut underwent ferroptosis. Mechanistically, molecular docking further established that Lut probably promoted the heme degradation and accumulation of labile iron pool (LIP) by excessively upregulating the HO-1 expression, which led to the Fenton reaction, GSH depletion, and lipid peroxidation in ccRCC, whereas blocking this signaling pathway evidently rescued the Lut-induced cell death of ccRCC by inhibiting ferroptosis. Altogether, the current study shows that the natural compound monomer Lut exerted anticancer efficacy by excessively upregulating HO-1 expression and activating LIP to trigger ferroptosis in ccRCC and could be a promising and potent drug candidate for ccRCC treatment.
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spelling pubmed-91539292022-06-01 HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation Han, Shangting Lin, Fangyou Qi, Yucheng Liu, Cong Zhou, Linxiang Xia, Yuqi Chen, Kang Xing, Ji Liu, Zilin Yu, Weimin Zhang, Yunlong Zhou, Xiangjun Rao, Ting Cheng, Fan Oxid Med Cell Longev Research Article Ferroptosis, a novel form of regulated cell death characterized by disrupted iron metabolism and the accumulation of lipid peroxides, has exhibited enormous potential in the therapy of cancer particularly clear cell renal cell carcinoma (ccRCC). Luteolin (Lut), a natural flavonoid widely existing in various fruits and vegetables, has been proven to exert potent anticancer activity in vitro and in vivo. However, previous studies on the anticancer mechanism of Lut have been shown in apoptosis but not ferroptosis. In the present study, we identified that Lut substantially inhibited the survival of ccRCC in vitro and in vivo, and this phenomenon was accompanied by excessively increased intracellular Fe(2+) and abnormal depletion of GSH. In addition, Lut induced the imbalance of mitochondrial membrane potential, classical morphological alterations of mitochondrial ferroptosis, generation of ROS, and occurrence of lipid peroxidation in an iron-dependent manner in ccRCC cells. However, these alterations induced by Lut could be reversed to some extent by the iron ion chelator deferiprone or the ferroptosis inhibitor ferrostatin-1, indicating that ccRCC cells treated with Lut underwent ferroptosis. Mechanistically, molecular docking further established that Lut probably promoted the heme degradation and accumulation of labile iron pool (LIP) by excessively upregulating the HO-1 expression, which led to the Fenton reaction, GSH depletion, and lipid peroxidation in ccRCC, whereas blocking this signaling pathway evidently rescued the Lut-induced cell death of ccRCC by inhibiting ferroptosis. Altogether, the current study shows that the natural compound monomer Lut exerted anticancer efficacy by excessively upregulating HO-1 expression and activating LIP to trigger ferroptosis in ccRCC and could be a promising and potent drug candidate for ccRCC treatment. Hindawi 2022-04-25 /pmc/articles/PMC9153929/ /pubmed/35656025 http://dx.doi.org/10.1155/2022/3846217 Text en Copyright © 2022 Shangting Han et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Han, Shangting
Lin, Fangyou
Qi, Yucheng
Liu, Cong
Zhou, Linxiang
Xia, Yuqi
Chen, Kang
Xing, Ji
Liu, Zilin
Yu, Weimin
Zhang, Yunlong
Zhou, Xiangjun
Rao, Ting
Cheng, Fan
HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
title HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
title_full HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
title_fullStr HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
title_full_unstemmed HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
title_short HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation
title_sort ho-1 contributes to luteolin-triggered ferroptosis in clear cell renal cell carcinoma via increasing the labile iron pool and promoting lipid peroxidation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153929/
https://www.ncbi.nlm.nih.gov/pubmed/35656025
http://dx.doi.org/10.1155/2022/3846217
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