Yang 2023 Cell Death Discov

Yang H, Gao Y, Xu D, Xu K, Liang SQ, Yang Z, Scherz A, Hall SRR, Forster S, Berezowska S, Yao F, Ochsenbein AF, Marti TM, Kocher GJ, Schmid RA, Dorn P, Peng RW (2023) MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma. https://doi.org/10.1038/s41420-023-01307-2

» Cell Death Discov 9:55. PMID: 36765038 Open Access

Yang Haitang, Gao Yanyun, Xu Duo, Xu Ke, Liang Shun-Qing, Yang Zhang, Scherz Amina, Hall Sean RR, Forster Stefan, Berezowska Sabina, Yao Feng, Ochsenbein Adrian F, Marti Thomas M, Kocher Gregor J, Schmid Ralph A, Dorn Patrick, Peng Ren-Wang (2023) Cell Death Discov

Abstract: 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.

• Bioblast editor: Plangger M

Labels: MiParea: Respiration  Pathology: Cancer  Stress:Oxidative stress;RONS  Organism: Human  Tissue;cell: Lung;gill, Endothelial;epithelial;mesothelial cell  Preparation: Intact cells 

Coupling state: ROUTINE 

HRR: Oxygraph-2k 

2023-02