Androgen Receptor Activation in Glioblastoma Can Be Achieved by Ligand-Independent Signaling through EGFR—A Potential Therapeutic Target

International Journal of Molecular Sciences

Michael Weller¹  Mijal Gutreiman²  Nomi Zalcman²  Iris Lavon²  Tal Shahar³ 

[1] Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital, University of Zurich, CH-8091 Zurich, Switzerland;Molecular Neuro-Oncology Laboratory, Leslie and Michael Gaffin Center for Neuro-Oncology, Agnes Ginges Center for Human Neurogenetics, Neurology Department, Hadassah Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel;The Laboratory for Molecular Neuro-Oncology, Department of Neurosurgery, Shaare Zedek-Hebrew University Medical Center, P.O. Box 3235, Jerusalem 9103102, Israel;

关键词: glioblastoma;    androgen receptor (AR);    epidermal growth factor receptor (EGFR);    protein kinase B (AKT);    AR antagonist;   

DOI  :  10.3390/ijms222010954

来源: DOAJ

【 摘 要 】

Androgen receptor (AR) is a ligand-mediated transcription factor that belongs to the superfamily of steroid receptors. AR is overexpressed in most glioblastomas and is a potential therapeutic target. In prostate and breast cancers, AR activation can be achieved also by a ligand-independent signaling through receptor tyrosine kinases such as epidermal growth factor receptor (EGFR). Considering its major role in glioblastoma, we explored whether EGFR is involved in AR signaling in this tumor. Analysis of mRNA expression in 28 glioblastoma samples with quantitative real-time reverse-transcription polymerase chain reaction revealed a positive and significant correlation between AR and EGFR mRNA expression levels (R = 0.47, p = 0.0092), which was validated by The Cancer Genome Atlas dataset (n = 671) analysis (R = 0.3, p = 0.00006). Using Western blotting and immunofluorescence staining, we showed that the transduced overexpression of EGFR or its variant EGFRvIII in the U87MG cells induced AR protein overexpression and nuclear translocation and Protein kinase B (AKT) S473 and AR S210/213 phosphorylation. The EGFR kinase inhibitor afatinib and the AKT inhibitor MK2206 reduced AR nuclear translocation. Afatinib diminished AKT phosphorylation at 30 min and 6 h in the EGFR- and EGFRvIII-overexpressing cells, respectively, and decreased AR phosphorylation in EGFR-overexpressing cells at 4 h. Afatinib or MK2206 combination therapy with the AR antagonist enzalutamide in the EGFR and EGFRvIII-overexpressing cells had synergistic efficacy. Our findings suggest that EGFR signaling is involved in AR activation in glioblastoma and buttresses the concept of combining an EGFR signaling inhibitor with AR antagonists as a potential glioblastoma treatment.

【 授权许可】

Unknown