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TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3
1Department of Pathology, George Whipple Laboratory for Cancer Research, Urology, Radiation Oncology, New York, NY, USA.
Background:
Both androgen receptor (AR) and orphan receptor TR2 (TR2) belong to the steroid nuclear receptor superfamily and are expressed in prostate cancer tissue and cell lines. AR has been known to be involved in prostate proliferation and prostate cancer progression. AR binds to androgen response elements and regulates target gene expression via a mechanism involving coregulators. However, the function of TR2 in prostate and prostate cancer and the relationship between TR2 and AR in the prostate cancer is unclear.
Methods:
Transient transfection and CAT reporter gene assays were employed to assess AR-mediated transactivation. The expression level of prostate specific antigen (PSA) was measured by Northern blot analysis. The interaction between AR and TR2 was assessed by glutathione-S-transferase (GST) pull-down assay and mammalian two-hybrid system assay.
Results:
Orphan nuclear receptor TR2 suppressed androgen-mediated transactivation in prostate cancer PC-3 cells, and over-expression of TR2 suppressed PSA expression. The suppression of AR mediated transactivation by TR2 is not due to competition for the limited coregulator availability by these two receptors, but possibly through the interaction between TR2 and AR nuclear receptors.
Conclusions:
TR2 may function as a negative modulator to suppress AR function in prostate cancer. Further studies on how to control TR2 function may result in the ability to modulate AR function in prostate cancer.
Insights
Orphan nuclear receptor TR2 suppresses androgen receptor (AR) activity in prostate cancer cells. This interaction may offer new ways to control AR function and treat prostate cancer.
Area of Science:
- Molecular Endocrinology
- Cancer Biology
- Nuclear Receptor Signaling
Background:
- Androgen receptor (AR) and orphan receptor TR2 (TR2) are nuclear receptors found in prostate cancer.
- AR drives prostate cancer progression, while TR2's role remains unclear.
Purpose of the Study:
- To investigate the function of TR2 in prostate cancer.
- To determine the relationship between TR2 and AR in prostate cancer.
Main Methods:
- Transient transfection and CAT reporter gene assays for AR transactivation.
- Northern blot analysis for prostate specific antigen (PSA) expression.
- Glutathione-S-transferase (GST) pull-down and mammalian two-hybrid assays for AR-TR2 interaction.
Main Results:
- TR2 suppressed AR-mediated transactivation and PSA expression in prostate cancer cells.
- TR2's suppression mechanism involves interaction with AR, not coregulator competition.
Conclusions:
- TR2 acts as a negative modulator of AR function in prostate cancer.
- Targeting TR2 could offer a novel strategy for modulating AR in prostate cancer treatment.