PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia

Autor: Tina M. Schnöder, Stefan Freigang, Georgia Konstantinidou, Ralph A. Schmid, Sabina Berezowska, Alessandro Rimessi, Paolo Pinton, Johanna Baumgartner, Chiara Pozzato, Florian H. Heidel, Maria Saliakoura, Matteo Rossi Sebastiano, Lukas Bubendorf, Spasenija Savic Prince
Jazyk: angličtina
Rok vydání: 2020
Předmět:
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
Zdroj: Nature cell biology
ISSN: 1476-4679
1465-7392
Popis: 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.
Databáze: OpenAIRE
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