The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Abstract

The major obstacle in the management of advanced prostate cancer is the occurrence of resistance to endocrine therapy. Although the androgen receptor (AR) has been linked to therapy failure, the underlying escape mechanisms have not been fully clarified. Being closely related to the AR, the glucocorticoid receptor (GR) has been suggested to play a role in enzalutamide and docetaxel resistance. Given that glucocorticoids are frequently applied to prostate cancer patients, it is essential to unravel the exact role of the GR in prostate cancer progression. Assessment of GR expression and functional significance in tissues from 177 prostate cancer patients, including 14 lymph node metastases, as well as in several human prostate cancer models, including androgen-dependent, androgen-independent, and long-term antiandrogen-treated cell lines. Although GR expression is reduced in primary prostate cancer tissue, it is restored in metastatic lesions. Relapse patients with high GR experience shortened progression-free survival. GR is significantly increased upon long-term abiraterone or enzalutamide treatment in the majority of preclinical models, thus identifying GR upregulation as an underlying mechanism for cells to bypass AR blockade. Importantly, GR inhibition by RNAi or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines. GR upregulation seems to be a common mechanism during antiandrogen treatment and supports the notion that targeting the GR pathway combined with antiandrogen medication may further improve prostate cancer therapy. .

Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

“…In the Enz‐resistant models, in addition to the increased AR levels, GR protein levels are also increased compared to the nonresistant cells . Surprisingly, inhibition of GR by the GR‐antagonist RU‐486 reduced both GR and AR protein levels . In addition, Abi treatment also reduced both GR and AR protein levels.…”

“…This cross‐talk between AR and GR to cross‐regulate their protein levels requires further analyses to ascertain whether the reduction of AR protein levels is due to the interdependence between AR stability and activated GR. Furthermore, combination of Abi and RU‐486 was more effective than the individual treatment in reducing PCa 3D‐spheroid growth, even in therapy resistant (Abi and Enz) models . Accordingly, simultaneous targeting of AR and GR using a chimeric molecule would be a beneficial option in a subgroup of patients with elevated AR and GR.…”

“…GR is another factor that confers resistance to Enz or Abi treatment . In the Enz‐resistant models, in addition to the increased AR levels, GR protein levels are also increased compared to the nonresistant cells . Surprisingly, inhibition of GR by the GR‐antagonist RU‐486 reduced both GR and AR protein levels .…”

“…Since the reduction of AR and GR protein levels was not the consequence of downregulation of their cognate mRNA expression. This indicates altered AR protein stability as the reason for resistance to Enz or Abi . This cross‐talk between AR and GR to cross‐regulate their protein levels requires further analyses to ascertain whether the reduction of AR protein levels is due to the interdependence between AR stability and activated GR.…”

“…17 Surprisingly, inhibition of GR by the GR-antagonist RU-486 reduced both GR and AR protein levels. 17 In addition, Abi treatment also reduced both GR and AR protein levels. Since the reduction of AR and GR protein levels was not the consequence of downregulation of their cognate mRNA expression.…”