Activation of β-Catenin by Oncogenic PIK3CA and EGFR Promotes Resistance to Glucose Deprivation by Inducing a Strong Antioxidant Response

被引：9

作者：

Cardone, Luca ^{[1
]}

Bardelli, Alberto ^{[2
,3
]}

Avvedimento, Vittorio Enrico ^{[1
]}

机构：

[1] Univ Naples Federico II, Sch Med, Dept Biol & Cellular & Mol Pathol, Naples, Italy

[2] Univ Turin, Sch Med, Inst Canc Res & Treatment, Mol Genet Lab, Turin, Italy

[3] FIRC Inst Mol Oncol IFOM, Milan, Italy

来源：

PLOS ONE | 2012年 / 7卷 / 05期

关键词：

GROWTH-FACTOR-RECEPTOR; TUMOR-CELL GROWTH; OXIDATIVE STRESS; PROTEIN-KINASE; BREAST-CANCER; HIGH-FREQUENCY; LUNG-CANCER; METABOLISM; MUTATIONS; GENE;

D O I：

10.1371/journal.pone.0037526

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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/beta-catenin and FOXO4 signalling. Our data highlights a new functional synergism between oncogenic EGFR and PIK3CA with WNT/beta-catenin conferring high tolerance to oxidative stress generated by nutrient deprivation.

引用

页数：13

共 47 条

[1] Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting β-catenin from T cell factor- to Forkhead box O-mediated transcription [J].