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Overexpression of macrophage stimulating 1 enhances the anti-tumor effects of IL-24 in esophageal cancer via inhibiting ERK-Mfn2 signaling-dependent mitophagy.

Authors
  • Zhang, Jianpeng1
  • Sun, Lin2
  • Li, Weiqiang3
  • Wang, Yanyu4
  • Li, Xinzhen5
  • Liu, Yang6
  • 1 Department of Thoracic Surgery, Beijing Luhe Hospital, Capital Medical University, 82 Xinhua South Road, Tongzhou District, Beijing, 101149, PR China. Electronic address: [email protected] , (China)
  • 2 Department of Thoracic Surgery, Beijing Luhe Hospital, Capital Medical University, 82 Xinhua South Road, Tongzhou District, Beijing, 101149, PR China. Electronic address: [email protected] , (China)
  • 3 Department of Thoracic Surgery, Beijing Luhe Hospital, Capital Medical University, 82 Xinhua South Road, Tongzhou District, Beijing, 101149, PR China. Electronic address: [email protected] , (China)
  • 4 Department of Thoracic Surgery, Beijing Luhe Hospital, Capital Medical University, 82 Xinhua South Road, Tongzhou District, Beijing, 101149, PR China. Electronic address: [email protected] , (China)
  • 5 Department of Thoracic Surgery, Beijing Luhe Hospital, Capital Medical University, 82 Xinhua South Road, Tongzhou District, Beijing, 101149, PR China. Electronic address: [email protected] , (China)
  • 6 Department of Thoracic Surgery, Beijing Luhe Hospital, Capital Medical University, 82 Xinhua South Road, Tongzhou District, Beijing, 101149, PR China. Electronic address: [email protected]com. , (China)
Type
Published Article
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Publication Date
Jun 01, 2019
Volume
114
Pages
108844–108844
Identifiers
DOI: 10.1016/j.biopha.2019.108844
PMID: 30981108
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Although cytokine-based therapy is a promising tool to control the progression of esophageal cancer, low therapeutic responses largely compromise treatment efficacy through unidentified mechanisms. The goal of our study was to explore the roles of macrophage stimulating 1 (Mst1) and mitophagy in enhancing IL-24-based cytokine therapy in esophageal cancer. Our data demonstrated that IL-24 application promoted cancer death by inducing mitochondrial stress, as manifested by mitochondrial ROS overproduction, mitochondrial potential dissipation, cellular ATP deprivation and mitochondrial death activation. Overexpression of Mst1 enhanced IL-24-mediated mitochondrial damage and further augmented IL-24-induced death in esophageal cancer. Molecular investigations illustrated that the IL-24-activated mitochondrial response is accompanied by activation of mitophagy, a protective mechanism to attenuate mitochondrial damage. However, Mst1 overexpression inhibited mitophagy activity, which was achieved by inactivating the ERK-Mfn2 signaling pathway. The re-activation of mitophagy abolished the cancer-killing effects of Mst1 overexpression on esophageal cancer. Altogether, our data demonstrate that IL-24-related therapeutic resistance is associated with mitophagy activation. Mst1 overexpression inhibits mitophagy activity via suppressing the ERK-Mfn2 pathway, ultimately augmenting IL-24-inducd esophageal cancer death via enhanced mitochondrial stress. Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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