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

Nat Cell Biol. 2020 Nov;22(11):1382-1395. doi: 10.1038/s41556-020-00592-8. Epub 2020 Oct 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adaptation, Physiological
  • Adenocarcinoma of Lung / enzymology*
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Cell Proliferation
  • Cell Survival
  • Energy Metabolism
  • Female
  • Humans
  • Lipid Peroxidation
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • Mutation*
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction
  • Tumor Hypoxia*


  • KRAS protein, human
  • PLCG1 protein, human
  • Phospholipase C gamma
  • Plcg1 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)