Abstract
Background: We showed previously that nuclear localization of the androgen receptor (AR) and expression of the androgen-responsive gene FK506-binding protein 5 (FKBP5) in esophageal adenocarcinoma (EAC) tissues were associated with decreased patient survival, suggesting a role for androgens in this cancer. Aim: To investigate the effect of the AR ligand 5α-dihydrotestosterone (DHT) on AR-expressing EAC cell lines in vitro. Methods and Results: In tissue resection specimens from EAC patients, FKBP5 expression was positively associated with proliferation as measured by Ki-67 expression. We stably transduced AR into three AR-negative EAC cell lines, OE33, JH-EsoAd1, and OE19, to investigate androgen signaling in vitro. In the AR-expressing cell lines, 10 nM DHT, the concentration typically used to study AR signaling, induced changes in the expression of androgen-responsive genes and inhibited proliferation by inducing cell cycle arrest and senescence. At lower DHT concentrations near the half maximal inhibitory concentration (IC50), the AR-expressing cell lines proliferated and there were changes in the expression of androgen-responsive genes. In direct co-culture with cancer-associated fibroblast-like PShTert myofibroblasts, 10 nM DHT induced changes in the expression of androgen-responsive genes but did not inhibit proliferation. Conclusions: This is the first study to show that EAC cell lines respond to androgen in vitro. Proliferation together with the expression of androgen-responsive genes was dependent on the concentration of DHT, or the presence of a permissive microenvironment, consistent with observations in the tissues. These findings are consistent with a role for androgen signaling in EAC.
Original language | English |
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Pages (from-to) | 3402-3414 |
Number of pages | 13 |
Journal | Digestive Diseases and Sciences |
Volume | 62 |
Issue number | 12 |
Early online date | 2017 |
DOIs | |
Publication status | Published - 1 Dec 2017 |
Keywords
- Androgen receptor
- Dihydrotestosterone
- Direct co-culture
- Esophageal adenocarcinoma
- Fibroblast
- FKBP5
- In vitro