The glucocorticoid receptor is a key player for prostate cancer cell survival and a target for improved anti-androgen therapy.

Purpose: The major obstacle in the management of advanced prostate cancer (PCa) 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 PCa patients, it is essential to unravel the exact role of the GR in PCa progression. Experimental Design: Assessment of GR expression and functional significance in tissues from 177 PCa patients, including 14 lymph-node metastases, as well as in several human PCa models including androgen-dependent, androgen-independent, and long-term anti-androgen-treated cell lines. Results: While GR expression is reduced in primary PCa 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 RNA-interference or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines. Conclusions: upregulation seems to be a common mechanism during anti-androgen treatment and supports the notion that targeting the GR pathway combined with anti-androgen medication may further improve PCa therapy.

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