Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress

Abstract Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. I...

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Autores principales:	Xinlai Cheng, Christiane Peuckert, Stefan Wölfl
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b5a8de17946a46a69f5deaff5b835776
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spelling	oai:doaj.org-article:b5a8de17946a46a69f5deaff5b8357762021-12-02T15:06:22ZEssential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress10.1038/s41598-017-15342-42045-2322https://doaj.org/article/b5a8de17946a46a69f5deaff5b8357762017-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-15342-4https://doaj.org/toc/2045-2322Abstract Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3Y705, little is known about Stat3S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3Y705F, but not Stat3S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38MAPK was involved and adding antioxidants, p38MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.Xinlai ChengChristiane PeuckertStefan WölflNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xinlai Cheng Christiane Peuckert Stefan Wölfl Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
description	Abstract Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3Y705, little is known about Stat3S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3Y705F, but not Stat3S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38MAPK was involved and adding antioxidants, p38MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.
format	article
author	Xinlai Cheng Christiane Peuckert Stefan Wölfl
author_facet	Xinlai Cheng Christiane Peuckert Stefan Wölfl
author_sort	Xinlai Cheng
title	Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
title_short	Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
title_full	Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
title_fullStr	Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
title_full_unstemmed	Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
title_sort	essential role of mitochondrial stat3 in p38mapk mediated apoptosis under oxidative stress
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b5a8de17946a46a69f5deaff5b835776
work_keys_str_mv	AT xinlaicheng essentialroleofmitochondrialstat3inp38mapkmediatedapoptosisunderoxidativestress AT christianepeuckert essentialroleofmitochondrialstat3inp38mapkmediatedapoptosisunderoxidativestress AT stefanwolfl essentialroleofmitochondrialstat3inp38mapkmediatedapoptosisunderoxidativestress
_version_	1718388474340442112

Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress

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