Saliakoura, Maria; Rossi Sebastiano, Matteo; Pozzato, Chiara; Heidel, Florian H.; Schnöder, Tina M.; Savic Prince, Spasenija; Bubendorf, Lukas; Pinton, Paolo; Schmid, Ralph A.; Baumgartner, Johanna; Freigang, Stefan; Berezowska, Sabina A.; Rimessi, Alessandro; Konstantinidou, Georgia (2020). PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia. Nature cell biology, 22(11), pp. 1382-1395. Springer Nature 10.1038/s41556-020-00592-8
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Konstantinidou_PLCy1 suppression promotes the adaptation.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (17MB) |
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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