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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http://dx.doi.org/10.1038/s41420-023-01307-2 | DOI Listing |
Front Oncol
December 2024
Cansearch Research Platform for Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Background: We previously demonstrated that APR-246 (eprenetapopt) could be an efficient treatment option against neuroblastoma (NB), the most common pediatric extracranial solid tumor. APR-246's mechanism of action is not completely understood and can differ between cell types. Here we investigate the involvement of well-known oncogenic pathways in NB's response to APR-246.
View Article and Find Full Text PDFAdv Sci (Weinh)
December 2024
Institute of Biomedical and Health Engineering, Shen Zhen Institutes of Advanced Technology, Chinese Academy of Science, Shenzhen, Guangdong, 518055, China.
Melanoma stem cells are a kind of cells with self-renewal and multi-directional differentiation potential. They are one of the key factors in the occurrence, development and metastasis of melanoma. This study demonstrates that MLLT3 is a transcription factor that regulates the stemness and progression of melanoma.
View Article and Find Full Text PDFAdv Sci (Weinh)
December 2024
Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, 400038, P. R. China.
Neuropathic pain, one of the most refractory pain diseases, remains a formidable medical challenge. There is still an unmet demand for effective and safe therapies to address this condition. Herein, a rat model of nerve injury-induced neuropathic pain is first established to explore its pathophysiological characteristics.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
Institute of Lipid Metabolism and Atherosclerosis, School of Pharmacy, Shandong Second Medical University, Weifang 261053, China. Electronic address:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to promote hyperlipidemia primarily by inducing the degradation of the low-density lipoprotein receptor. Notably, recent studies have demonstrated that PCSK9 promotes inflammation in the vascular system, however, the roles of PCSK9 in hepatic inflammation remain unclear. As PCSK9 is primarily expressed in the liver, this study aimed to elucidate the roles of PCSK9 and the underlying mechanisms in lipopolysaccharide (LPS)-challenged hepatocytes.
View Article and Find Full Text PDFBiochem Pharmacol
December 2024
The National Clinical Research Center for Kidney Diseases, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China. Electronic address:
Podocyte injury leads to proteinuria and glomerular diseases. Different podocyte injuries have distinct mechanisms. It is desirable to use a regimen that targets the mechanism of a given podocyte injury for a specific and improved result.
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