Journal Article

The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer

Persson, Jenny L., Mandel, Anna, Syed Khaja, Azharuddin Sajid, Larsson, Per, Sarwar, Martuza, Semenas, Julius

2018

Overview

Background Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGF) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. In this study, we uncovered the molecular mechanisms underlying the interconnection among the androgen receptor (AR), matrix metalloproteinase-9 (MMP9) and EGFR in promoting PCa progression. Methods Immunohistochemical analysis of the tissue microarrays consisting of primary and metastatic PCa tissues was performed. The clinical importance of EGFR and its association with survivals were analyzed using three cohorts from MSKCC Prostate Oncogenome Project dataset (For primary tumors, n  = 181; for metastatic tumors n  = 37) and The Cancer Genome Atlas Prostate Adenocarcinoma Provisional dataset ( n  = 495). Targeted overexpression or inhibition of the proteins of interests was introduced into PCa cell lines. Treatment of PCa cell lines with the compounds was conducted. Immunoblot analysis was performed. Results We showed that AR, MMP-9 and EGFR are interconnect factors, which may cooperatively promote PCa progression. Altered EGFR expression was associated with poor disease-free survival in PCa patients. Induced overexpression of AR led to an increase in the expression of EGFR, p-GSK-3β and decrease in p27 expression in PCa cell lines in the presence of androgen stimulation. Overexpression of MMP9 significantly induced EGFR expression in PCa cells. Inhibition of PIP5K1α, a lipid kinase that acts upstream of PI3K/AKT greatly reduced expressions of AR, MMP-9 and EGFR. Conclusions Our findings also suggest that PCa cells may utilize AR, EGFR and MMP-9 pathways in androgen-dependent as well as in castration-resistant conditions. Our data suggest a new therapeutic potential to block cancer metastasis by targeting AR, EGFR and MMP-9 pathways in subsets of PCa patients.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Androgen receptor and androgen / Androgens / Basic Medicine / Biomedical and Life Sciences / Biomedicine / Bone marrow / Cancer metastasis / Cell Line, Tumor / Datasets / Epidermal growth factor / Epidermal growth factor receptor / ErbB Receptors - metabolism / Fibroblasts / Gene expression / Humans / Investigations / Kinases / Ligands / Lung cancer / Lymphatic system / Male / Matrix Metalloproteinase 9 - metabolism / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / Metastasis / Molecular Medicine / Phosphorylation / Prostate cancer / Prostatic Neoplasms - metabolism / Receptors, Androgen - metabolism / Research Article / Signal Transduction / Tumors / Vascular endothelial growth factor