PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia
Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLCγ1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCγ1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca2+ entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function of Plcg1 in a mouse model of KrasG12D-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLCγ1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Nature cell biology - 22(2020), 11 vom: 19. Nov., Seite 1382-1395 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Saliakoura, Maria [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.01.2021 Date Revised 05.10.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41556-020-00592-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316472301 |
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| 100 | 1 | |a Saliakoura, Maria |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia |
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| 520 | |a Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLCγ1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCγ1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca2+ entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function of Plcg1 in a mouse model of KrasG12D-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLCγ1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value | ||
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| 700 | 1 | |a Rossi Sebastiano, Matteo |e verfasserin |4 aut | |
| 700 | 1 | |a Pozzato, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Heidel, Florian H |e verfasserin |4 aut | |
| 700 | 1 | |a Schnöder, Tina M |e verfasserin |4 aut | |
| 700 | 1 | |a Savic Prince, Spasenija |e verfasserin |4 aut | |
| 700 | 1 | |a Bubendorf, Lukas |e verfasserin |4 aut | |
| 700 | 1 | |a Pinton, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a A Schmid, Ralph |e verfasserin |4 aut | |
| 700 | 1 | |a Baumgartner, Johanna |e verfasserin |4 aut | |
| 700 | 1 | |a Freigang, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Berezowska, Sabina A |e verfasserin |4 aut | |
| 700 | 1 | |a Rimessi, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Konstantinidou, Georgia |e verfasserin |4 aut | |
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