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PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia
- Source :
- Nature cell biology
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Male
Lung Neoplasms
lipid droplets
Mitochondrion
RAS transformed cells
medicine.disease_cause
Transgenic
stress
Mice
0302 clinical medicine
Mice, Inbred NOD
610 Medicine & health
induction
fatty acid oxidation
0303 health sciences
growth factor
Adaptation, Physiological
Cell biology
Mitochondria
030220 oncology & carcinogenesis
Adenocarcinoma
Female
KRAS
medicine.symptom
cancer calcium
Signal Transduction
Cell Survival
Physiological
Socio-culturale
Adenocarcinoma of Lung
Mice, Transgenic
Biology
Article
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
stress, phospholipase C gamma, RAS transformed cells, fatty acid oxidation, lipid droplets, growth factor, cancer calcium, activation, induction
medicine
Animals
Humans
Adaptation
030304 developmental biology
Cell Proliferation
Tumor hypoxia
Cell growth
Phospholipase C gamma
Cell Biology
Hypoxia (medical)
medicine.disease
Apoptosis
A549 Cells
Cancer cell
Mutation
Inbred NOD
570 Life sciences
biology
Tumor Hypoxia
activation
Lipid Peroxidation
Energy Metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 14764679 and 14657392
- Volume :
- 22
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature cell biology
- Accession number :
- edsair.doi.dedup.....c88a8cf87cf85ca3eae09578968f3e1f