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.

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

Rossi Sebastiano M.;
2020-01-01

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.
2020
22
11
1382
1395
A549 Cells; Adaptation, Physiological; Adenocarcinoma of Lung; Animals; Cell Proliferation; Cell Survival; Energy Metabolism; Female; Humans; Lipid Peroxidation; Lung Neoplasms; Male; Mice, Inbred NOD; Mice, Transgenic; Mitochondria; Phospholipase C gamma; Proto-Oncogene Proteins p21(ras); Signal Transduction; Mutation; Tumor Hypoxia
Saliakoura M.; Rossi Sebastiano M.; Pozzato C.; Heidel F.H.; Schnoder T.M.; Savic Prince S.; Bubendorf L.; Pinton P.; A. Schmid R.; Baumgartner J.; Fr...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1853586
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