Connexin 43 C‐terminus directly inhibits the hyperphosphorylation of Akt/ERK through protein–protein interactions in glioblastoma

• Published in: Cancer science 2018-08, Vol.109 (8), p.2611-2622
• Main Authors: Kuang, Jing‐Ya, Guo, Yu‐Feng, Chen, Ying, Wang, Jun, Duan, Jiang‐Jie, He, Xiao‐Li, Li, Lin, Yu, Shi‐Cang, Bian, Xiu‐Wu
• Format: Article
• Language: English
• Subjects: Adenoviruses; Akt; AKT protein; Antibodies; Cancer therapies; Cell Line, Tumor; Connexin 43; Connexin 43 - genetics; Epidermal growth factor; epidermal growth factor receptor; Epidermal growth factor receptors; ErbB Receptors - genetics; ERK; Extracellular signal-regulated kinase; Gene expression; Genomes; Glioblastoma; Glioblastoma - genetics; Humans; Kinases; MAP Kinase Signaling System - genetics; Medical prognosis; Molecular modelling; Nervous system; Original; Patients; Peptides; Phosphorylation; Phosphorylation - genetics; Protein interaction; Protein Interaction Domains and Motifs - genetics; Proteins; Proto-Oncogene Proteins c-akt - genetics; R&D; Research & development; Signal transduction; Signal Transduction - genetics; Software; Stem cells; Studies; Survival analysis; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13707

Although the deregulation of epidermal growth factor receptor (EGFR) is one of the most common molecular mechanisms of glioblastoma (GBM) pathogenesis, the efficacy of anti‐EGFR therapy is limited. Additionally, response to anti‐EGFR therapy is not solely dependent on EGFR expression and is more promising in patients with reduced activity of EGFR downstream signaling pathways. Thus, there is considerable interest in identifying the compensatory regulatory factors of the EGFR signaling pathway to improve the efficacy of anti‐EGFR therapies for GBM. In this study, we confirmed the low efficacy of EGFR inhibitors in GBM patients by meta‐analysis. We then identified a negative correlation between connexin 43 (Cx43) expression and Akt/ERK activation, which was caused by the direct interactions between Akt/ERK and Cx43. By comparing the interactions between Akt/ERK and Cx43 using a series of truncated and mutated Cx43 variants, we revealed that the residues T286/A305/Q308/Y313 and S272/S273 at the carboxy terminus of Cx43 are critical for its binding with Akt and ERK, respectively. In addition, Kaplan–Meier survival analysis using data from The Cancer Genome Atlas datasets indicated that the expression of Cx43 significantly improved the prognosis of GBM patients who express EGFR. Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of EGFR inhibitor treatments for GBM. Targeting the interaction between the carboxy terminus of Cx43 and Akt/ERK could be an effective therapeutic strategy against GBM. Connexin 43 (Cx43) C‐terminus was found to directly interact with Akt and ERK1/2 to inhibit their hyperphosphorylation and to attenuate the activation of the epidermal growth factor/epidermal growth factor receptor signaling pathway, indicating the potential of Cx43 as a marker for predicting the efficacy of epidermal growth factor receptor inhibitor treatments for glioblastoma.