Open AccessPLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia
Author(s) -
Maria Saliakoura,
Matteo Rossi Sebastiano,
Chiara Pozzato,
Florian H. Heidel,
Tina M. Schnöder,
Spasenija Savic Prince,
Lukas Bubendorf,
Paolo Pinton,
Ralph A. Schmid,
Johanna Baumgartner,
Stefan Freigang,
Sabina Berezowska,
Alessandro Rimessi,
Georgia Konstantinidou
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-00592-8
Subject(s) - kras , hypoxia (environmental) , biology , cancer research , glycolysis , cell growth , adenocarcinoma , apoptosis , microbiology and biotechnology , cancer cell , lung cancer , mitochondrion , cancer , chemistry , medicine , endocrinology , metabolism , mutation , biochemistry , gene , oxygen , genetics , organic chemistry
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 Ca 2+ 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.