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

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 Kras^G12D-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.

SUBMITTER: Saliakoura M 

PROVIDER: S-EPMC7610419 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature