Ferroptosis is a lysosomal cell death process

Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. While impaired ferroptosis is tightly linked to human diseases and conditions, the mechanism and regulation of ferroptosis remain largely unknown. Here, we demonstrate that STAT3 is a positive regu...

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Veröffentlicht in:	Biochemical and biophysical research communications 2018-09, Vol.503 (3), p.1550-1556
Hauptverfasser:	Gao, Huan, Bai, Yuansong, Jia, Yuanyuan, Zhao, Yanan, Kang, Rui, Tang, Daolin, Dai, Enyong
Format:	Artikel
Sprache:	eng
Schlagworte:	60 APPLIED LIFE SCIENCES Animals APOPTOSIS Apoptosis - drug effects Autophagy CARCINOMAS Cathepsin CATHEPSINS Cell Death - drug effects Dogs Ferroptosis HUMAN POPULATIONS Humans Lysosomal cell death LYSOSOMES Lysosomes - metabolism Lysosomes - pathology PANCREAS Piperazines - pharmacology STAT3 STAT3 Transcription Factor - metabolism Tumor Cells, Cultured
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container_title	Biochemical and biophysical research communications
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creator	Gao, Huan Bai, Yuansong Jia, Yuanyuan Zhao, Yanan Kang, Rui Tang, Daolin Dai, Enyong
description	Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. While impaired ferroptosis is tightly linked to human diseases and conditions, the mechanism and regulation of ferroptosis remain largely unknown. Here, we demonstrate that STAT3 is a positive regulator of ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Activation of the MAPK/ERK pathway, but not inhibition of system Xc−, was required for STAT3 activation during erastin-induced ferroptosis. Importantly, pharmacological inhibition and genetic silencing of STAT3 through small molecules (e.g., cryptotanshinone and S3I-201) or siRNA blocked erastin-induced ferroptosis in PDAC cells. Mechanically, STAT3-mediated cathepsin B expression was required for ferroptosis. Consequently, inhibition of lysosome-dependent cell death by pharmacological blockade of cathepsin activity (using CA-074Me) or vacuolar type H+-ATPase (using bafilomycin A1) limited erastin-induced ferroptosis. These studies indicate that ferroptosis is a lysosomal cell death process.
doi_str_mv	10.1016/j.bbrc.2018.07.078
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While impaired ferroptosis is tightly linked to human diseases and conditions, the mechanism and regulation of ferroptosis remain largely unknown. Here, we demonstrate that STAT3 is a positive regulator of ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Activation of the MAPK/ERK pathway, but not inhibition of system Xc−, was required for STAT3 activation during erastin-induced ferroptosis. Importantly, pharmacological inhibition and genetic silencing of STAT3 through small molecules (e.g., cryptotanshinone and S3I-201) or siRNA blocked erastin-induced ferroptosis in PDAC cells. Mechanically, STAT3-mediated cathepsin B expression was required for ferroptosis. Consequently, inhibition of lysosome-dependent cell death by pharmacological blockade of cathepsin activity (using CA-074Me) or vacuolar type H+-ATPase (using bafilomycin A1) limited erastin-induced ferroptosis. 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While impaired ferroptosis is tightly linked to human diseases and conditions, the mechanism and regulation of ferroptosis remain largely unknown. Here, we demonstrate that STAT3 is a positive regulator of ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Activation of the MAPK/ERK pathway, but not inhibition of system Xc−, was required for STAT3 activation during erastin-induced ferroptosis. Importantly, pharmacological inhibition and genetic silencing of STAT3 through small molecules (e.g., cryptotanshinone and S3I-201) or siRNA blocked erastin-induced ferroptosis in PDAC cells. Mechanically, STAT3-mediated cathepsin B expression was required for ferroptosis. Consequently, inhibition of lysosome-dependent cell death by pharmacological blockade of cathepsin activity (using CA-074Me) or vacuolar type H+-ATPase (using bafilomycin A1) limited erastin-induced ferroptosis. 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subjects	60 APPLIED LIFE SCIENCES Animals APOPTOSIS Apoptosis - drug effects Autophagy CARCINOMAS Cathepsin CATHEPSINS Cell Death - drug effects Dogs Ferroptosis HUMAN POPULATIONS Humans Lysosomal cell death LYSOSOMES Lysosomes - metabolism Lysosomes - pathology PANCREAS Piperazines - pharmacology STAT3 STAT3 Transcription Factor - metabolism Tumor Cells, Cultured
title	Ferroptosis is a lysosomal cell death process
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