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Increased androgen receptor levels and signaling in ovarian cancer cells by VEPH1 associated with suppression of SMAD3 and AKT activation
•VEPH1 increases androgen receptor levels and activity in ovarian cancer cells.•VEPH1 decreases SMAD3 levels and AKT activation in ovarian cancer cells.•AKT activation decreases androgen receptor levels in ovarian cancer cells.•SMAD3, at either high and low expression levels, decreases androgen rece...
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Published in: | The Journal of steroid biochemistry and molecular biology 2020-02, Vol.196, p.105498-105498, Article 105498 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | •VEPH1 increases androgen receptor levels and activity in ovarian cancer cells.•VEPH1 decreases SMAD3 levels and AKT activation in ovarian cancer cells.•AKT activation decreases androgen receptor levels in ovarian cancer cells.•SMAD3, at either high and low expression levels, decreases androgen receptor levels.•VEPH1 interacts with the androgen receptor.
Studies indicate androgens contribute to initiation or progression of epithelial ovarian cancer through poorly understood mechanisms. We provide evidence that the androgen receptor (AR) interacts in a ligand-independent manner with the putative armadillo repeat domain of ventricular zone expressed PH domain-containing 1 (VEPH1). This interaction was increased by mutation of the two nuclear receptor-interacting LxxLL motifs present within the VEPH1 armadillo repeat domain. Androgen treatment did not result in nuclear co-localization of VEPH1 with AR, suggesting that VEPH1 does not function as a nuclear co-regulatory protein. VEPH1 expression decreased SMAD3 and activated AKT levels in ovarian cancer cell lines and increased AR activity and protein levels, consistent with an impact on receptor stability. Treatment of cells with dihydrotestosterone (DHT) increased AR protein levels measured 24 h after treatment, an effect augmented in VEPH1-transfected cells, and inhibited by knock-down of endogenous VEPH1. SMAD3 overexpression decreased AR protein levels and prevented the VEPH1-dependent increase in AR; however, silencing of SMAD3 paradoxically also decreased AR levels. DHT treatment led to a rapid and sustained decrease in phosphorylated AKT (pAKT) levels that was enhanced by VEPH1 expression. Inhibition of PI3K resulted in increased AR protein levels. These studies indicate that VEPH1 acts to enhance AR activity in ovarian cancer cells by decreasing SMAD3 and pAKT levels, resulting in increased levels of AR protein. |
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ISSN: | 0960-0760 1879-1220 |
DOI: | 10.1016/j.jsbmb.2019.105498 |