Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis

Abstract Background Platinum‐based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. M...

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Autores principales:	Wenwen Liu, Yang Zhou, Wenzhe Duan, Jing Song, Song Wei, Shengkai Xia, Yingyan Wang, Xiaohui Du, Encheng Li, Caixia Ren, Wei Wang, Qimin Zhan, Qi Wang
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	brain metastasis chemotherapeutic resistance ferroptosis glutathione metabolism GPX4 inhibitor lung cancer Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/79caf3b7d343462394b0bdca71b518fb
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spelling	oai:doaj.org-article:79caf3b7d343462394b0bdca71b518fb2021-11-11T12:06:40ZGlutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis2001-132610.1002/ctm2.517https://doaj.org/article/79caf3b7d343462394b0bdca71b518fb2021-09-01T00:00:00Zhttps://doi.org/10.1002/ctm2.517https://doaj.org/toc/2001-1326Abstract Background Platinum‐based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. Methods Platinum drug‐sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain‐of‐function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay. Results The derivative brain metastatic subpopulations (PC9‐BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM. Conclusions Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.Wenwen LiuYang ZhouWenzhe DuanJing SongSong WeiShengkai XiaYingyan WangXiaohui DuEncheng LiCaixia RenWei WangQimin ZhanQi WangWileyarticlebrain metastasischemotherapeutic resistanceferroptosisglutathione metabolismGPX4 inhibitorlung cancerMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 9, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	brain metastasis chemotherapeutic resistance ferroptosis glutathione metabolism GPX4 inhibitor lung cancer Medicine (General) R5-920
spellingShingle	brain metastasis chemotherapeutic resistance ferroptosis glutathione metabolism GPX4 inhibitor lung cancer Medicine (General) R5-920 Wenwen Liu Yang Zhou Wenzhe Duan Jing Song Song Wei Shengkai Xia Yingyan Wang Xiaohui Du Encheng Li Caixia Ren Wei Wang Qimin Zhan Qi Wang Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
description	Abstract Background Platinum‐based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown. Methods Platinum drug‐sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated upregulated proteins (GPX4 and GSTM1) in BM were identified by integrated metabolomics and proteomics in cell lines and verified by clinical serum sample. Gain‐of‐function and rescue experiments were implemented to reveal the impact and mechanism of GPX4 and GSTM1 on the chemosensitivity in BM. The interaction between GPX4 and GSTM1 was examined by immunoblotting and immunoprecipitation. The mechanism of upregulation of GPX4 was further uncovered by luciferase reporter assay, immunoprecipitation, and electrophoretic mobility shift assay. Results The derivative brain metastatic subpopulations (PC9‐BrMs) of parental cells PC9 developed obvious resistance to platinum. Radically altered profiles of BM metabolism and protein expression compared with primary lung cancer cells were described and GPX4 and GSTM1 were identified as being responsible for the high consumption of GSH, leading to decreased chemosensitivity by negatively regulating ferroptosis. Besides, GSTM1 was found regulated by GPX4, which was transcriptionally activated by the Wnt/NR2F2 signaling axis in BM. Conclusions Collectively, our findings demonstrated that Wnt/NR2F2/GPX4 promoted acquired chemoresistance by suppressing ferroptosis with high consumption of GSH. GPX4 inhibitor was found to augment the anticancer effect of platinum drugs in lung cancer BM, providing novel strategies for lung cancer patients with BM.
format	article
author	Wenwen Liu Yang Zhou Wenzhe Duan Jing Song Song Wei Shengkai Xia Yingyan Wang Xiaohui Du Encheng Li Caixia Ren Wei Wang Qimin Zhan Qi Wang
author_facet	Wenwen Liu Yang Zhou Wenzhe Duan Jing Song Song Wei Shengkai Xia Yingyan Wang Xiaohui Du Encheng Li Caixia Ren Wei Wang Qimin Zhan Qi Wang
author_sort	Wenwen Liu
title	Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
title_short	Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
title_full	Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
title_fullStr	Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
title_full_unstemmed	Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
title_sort	glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/79caf3b7d343462394b0bdca71b518fb
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Glutathione peroxidase 4‐dependent glutathione high‐consumption drives acquired platinum chemoresistance in lung cancer‐derived brain metastasis

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