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MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS...

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Autores principales: Yang, Haitang, Gao, Yanyun, Xu, Duo, Xu, Ke, Liang, Shun-Qing, Yang, Zhang, Scherz, Amina, Hall, Sean R. R., Forster, Stefan, Berezowska, Sabina, Yao, Feng, Ochsenbein, Adrian F., Marti, Thomas M., Kocher, Gregor J., Schmid, Ralph A., Dorn, Patrick, Peng, Ren-Wang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918536/
https://www.ncbi.nlm.nih.gov/pubmed/36765038
http://dx.doi.org/10.1038/s41420-023-01307-2
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author Yang, Haitang
Gao, Yanyun
Xu, Duo
Xu, Ke
Liang, Shun-Qing
Yang, Zhang
Scherz, Amina
Hall, Sean R. R.
Forster, Stefan
Berezowska, Sabina
Yao, Feng
Ochsenbein, Adrian F.
Marti, Thomas M.
Kocher, Gregor J.
Schmid, Ralph A.
Dorn, Patrick
Peng, Ren-Wang
author_facet Yang, Haitang
Gao, Yanyun
Xu, Duo
Xu, Ke
Liang, Shun-Qing
Yang, Zhang
Scherz, Amina
Hall, Sean R. R.
Forster, Stefan
Berezowska, Sabina
Yao, Feng
Ochsenbein, Adrian F.
Marti, Thomas M.
Kocher, Gregor J.
Schmid, Ralph A.
Dorn, Patrick
Peng, Ren-Wang
author_sort Yang, Haitang
collection PubMed
description Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.
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spelling pubmed-99185362023-02-12 MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma Yang, Haitang Gao, Yanyun Xu, Duo Xu, Ke Liang, Shun-Qing Yang, Zhang Scherz, Amina Hall, Sean R. R. Forster, Stefan Berezowska, Sabina Yao, Feng Ochsenbein, Adrian F. Marti, Thomas M. Kocher, Gregor J. Schmid, Ralph A. Dorn, Patrick Peng, Ren-Wang Cell Death Discov Article Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis. Nature Publishing Group UK 2023-02-10 /pmc/articles/PMC9918536/ /pubmed/36765038 http://dx.doi.org/10.1038/s41420-023-01307-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Yang, Haitang
Gao, Yanyun
Xu, Duo
Xu, Ke
Liang, Shun-Qing
Yang, Zhang
Scherz, Amina
Hall, Sean R. R.
Forster, Stefan
Berezowska, Sabina
Yao, Feng
Ochsenbein, Adrian F.
Marti, Thomas M.
Kocher, Gregor J.
Schmid, Ralph A.
Dorn, Patrick
Peng, Ren-Wang
MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
title MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
title_full MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
title_fullStr MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
title_full_unstemmed MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
title_short MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
title_sort mek1 drives oncogenic signaling and interacts with parp1 for genomic and metabolic homeostasis in malignant pleural mesothelioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918536/
https://www.ncbi.nlm.nih.gov/pubmed/36765038
http://dx.doi.org/10.1038/s41420-023-01307-2
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