| First Author | Saliakoura M | Year | 2020 |
| Journal | Nat Cell Biol | Volume | 22 |
| Issue | 11 | Pages | 1382-1395 |
| PubMed ID | 33077911 | Mgi Jnum | J:306022 |
| Mgi Id | MGI:6709590 | Doi | 10.1038/s41556-020-00592-8 |
| Citation | Saliakoura M, et al. (2020) PLCgamma1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia. Nat Cell Biol 22(11):1382-1395 |
| abstractText | 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 PLCgamma1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCgamma1 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 PLCgamma1 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. |
