Combinational therapy targeting the MET-mTOR-ROS loop disrupts mitochondrial autoregulatory machinery of liver cancer
© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics..
A wide variety of regulators have been identified in mechanistic target of rapamycin (mTOR) activation; however, the protective mechanisms of mTOR inactivation are still largely unknown, especially in tumor growth. Here, we have found the hepatocyte growth factor (HGF) receptor (MET) is required for mTOR activation-stimulated mitochondrial oxidative phosphorylation (OXPHOS) in a phosphorylation-dependent manner in liver cancer. Intriguingly, we observed mitochondrial quality dictates the regulatory effects of MET on mTOR and OXPHOS. Once overloaded, mitochondrial reactive oxygen species (ROS) inhibits mTOR activity and OXPHOS performance to prevent mitochondrial dysfunction-induced tumor cell death, by disrupting MET dimerization to block its autophosphorylation and interaction with vacuolar ATP synthase (V-ATPase). The MET-mTOR-ROS loop acts as a protective checkpoint in liver cancer, and thus this autoregulatory machinery is a promising combinational target for liver cancer therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Clinical and translational medicine - 10(2020), 8 vom: 18. Dez., Seite e237 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Xing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 04.11.2023 published: Print Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1002/ctm2.237 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319417948 |
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| 520 | |a © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. | ||
| 520 | |a A wide variety of regulators have been identified in mechanistic target of rapamycin (mTOR) activation; however, the protective mechanisms of mTOR inactivation are still largely unknown, especially in tumor growth. Here, we have found the hepatocyte growth factor (HGF) receptor (MET) is required for mTOR activation-stimulated mitochondrial oxidative phosphorylation (OXPHOS) in a phosphorylation-dependent manner in liver cancer. Intriguingly, we observed mitochondrial quality dictates the regulatory effects of MET on mTOR and OXPHOS. Once overloaded, mitochondrial reactive oxygen species (ROS) inhibits mTOR activity and OXPHOS performance to prevent mitochondrial dysfunction-induced tumor cell death, by disrupting MET dimerization to block its autophosphorylation and interaction with vacuolar ATP synthase (V-ATPase). The MET-mTOR-ROS loop acts as a protective checkpoint in liver cancer, and thus this autoregulatory machinery is a promising combinational target for liver cancer therapy | ||
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| 700 | 1 | |a Liang, Tingbo |e verfasserin |4 aut | |
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