ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic ta...

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Autores principales:	Wenbin Huang, Kunling Chen, Yishi Lu, Donghui Zhang, Yuan Cheng, Liuran Li, Weimei Huang, Guolin He, Hangyu Liao, Lei Cai, Yujun Tang, Liang Zhao, Mingxin Pan
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Hepatocellular carcinoma Sorafenib ABCC5 Ferroptosis Acquired resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/7fc3e1c3b68146b586da3b4215746095
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spelling	oai:doaj.org-article:7fc3e1c3b68146b586da3b42157460952021-11-30T04:14:38ZABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma1476-558610.1016/j.neo.2021.11.002https://doaj.org/article/7fc3e1c3b68146b586da3b42157460952021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1476558621000919https://doaj.org/toc/1476-5586Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic target of acquired sorafenib resistance in human hepatocellular carcinoma cells. The expression of ABCC5 was dramatically induced in sorafenib-resistant HCC cells and was remarkably associated with poor clinical prognoses. The down-regulation of ABCC5 expression could significantly reduce the resistance of sorafenib to HCC cells. Importantly, activation of PI3K/AKT/NRF2 axis was essential for sorafenib to induce ABCC5 expression. ABCC5 increased intracellular glutathione (GSH) and attenuated lipid peroxidation accumulation by stabilizing SLC7A11 protein, which inhibited ferroptosis. Additionally, the inhibition of ABCC5 enhanced the anti-cancer activity of sorafenib in vitro and in vivo. These findings demonstrate a novel molecular mechanism of acquired sorafenib resistance and also suggest that ABCC5 is a new regulator of ferroptosis in HCC cells.Wenbin HuangKunling ChenYishi LuDonghui ZhangYuan ChengLiuran LiWeimei HuangGuolin HeHangyu LiaoLei CaiYujun TangLiang ZhaoMingxin PanElsevierarticleHepatocellular carcinomaSorafenibABCC5FerroptosisAcquired resistanceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 23, Iss 12, Pp 1227-1239 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hepatocellular carcinoma Sorafenib ABCC5 Ferroptosis Acquired resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Hepatocellular carcinoma Sorafenib ABCC5 Ferroptosis Acquired resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Wenbin Huang Kunling Chen Yishi Lu Donghui Zhang Yuan Cheng Liuran Li Weimei Huang Guolin He Hangyu Liao Lei Cai Yujun Tang Liang Zhao Mingxin Pan ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma
description	Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic target of acquired sorafenib resistance in human hepatocellular carcinoma cells. The expression of ABCC5 was dramatically induced in sorafenib-resistant HCC cells and was remarkably associated with poor clinical prognoses. The down-regulation of ABCC5 expression could significantly reduce the resistance of sorafenib to HCC cells. Importantly, activation of PI3K/AKT/NRF2 axis was essential for sorafenib to induce ABCC5 expression. ABCC5 increased intracellular glutathione (GSH) and attenuated lipid peroxidation accumulation by stabilizing SLC7A11 protein, which inhibited ferroptosis. Additionally, the inhibition of ABCC5 enhanced the anti-cancer activity of sorafenib in vitro and in vivo. These findings demonstrate a novel molecular mechanism of acquired sorafenib resistance and also suggest that ABCC5 is a new regulator of ferroptosis in HCC cells.
format	article
author	Wenbin Huang Kunling Chen Yishi Lu Donghui Zhang Yuan Cheng Liuran Li Weimei Huang Guolin He Hangyu Liao Lei Cai Yujun Tang Liang Zhao Mingxin Pan
author_facet	Wenbin Huang Kunling Chen Yishi Lu Donghui Zhang Yuan Cheng Liuran Li Weimei Huang Guolin He Hangyu Liao Lei Cai Yujun Tang Liang Zhao Mingxin Pan
author_sort	Wenbin Huang
title	ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma
title_short	ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma
title_full	ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma
title_fullStr	ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma
title_full_unstemmed	ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma
title_sort	abcc5 facilitates the acquired resistance of sorafenib through the inhibition of slc7a11-induced ferroptosis in hepatocellular carcinoma
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/7fc3e1c3b68146b586da3b4215746095
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ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma

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