Activation of β-catenin by oncogenic PIK3CA and EGFR promotes resistance to glucose deprivation by inducing a strong antioxidant response.
Glucose is an essential fuel for cell survival and its availability limits aberrant cellular proliferation. We have hypothesized that specific cancer mutations regulate metabolic response(s) to glucose deprivation (GD). By means of somatic knock-in cellular models, we have analyzed the response to glucose deprivation in cells carrying the frequent (delE746-A750)EGFR, (G13D)KRAS or (E545K)PIK3CA cancer alleles. We demonstrate that, in mammary epithelial cells, glucose has an essential antioxidant function and that these cells are very sensitive to GD. Conversely, isogenic cells carrying the (delE746-A750)EGFR or the (E545K)PIK3CA, but not the (G13D)KRAS allele, display high tolerance to GD by stimulating the expression of anti-oxidant genes (MnSOD and catalase). This adaptive transcriptional response is mediated by the activation of WNT/β-catenin and FOXO4 signalling. Our data highlights a new functional synergism between oncogenic EGFR and PIK3CA with WNT/β-catenin conferring high tolerance to oxidative stress generated by nutrient deprivation.
Department of Biology and Cellular and Molecular Pathology, School of Medicine, University Federico II of Naples, Naples, Italy. lcardone@tigem.it
Luca
L
Cardone
Alberto
A
Bardelli
Vittorio Enrico
VE
Avvedimento
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000483:Alleles; D000975:Antioxidants / Q000378:metabolism; D018797:Cell Cycle Proteins; D016923:Cell Death; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D005947:Glucose / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D000975:Antioxidants; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051858:Forkhead Transcription Factors; D005947:Glucose; D005978:Glutathione; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D013482:Superoxide Dismutase; D014157:Transcription Factors; D051176:beta Catenin; C108803:FOXO4 protein, human; C484760:PIK3CA protein, human