Glucocorticoid Receptor (GR) Activation Is Associated with Increased cAMP/PKA Signaling in Castration-Resistant...

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Castration-resistant prostate cancer (CRPC) can develop resistance to androgen receptor signaling inhibition (ARSi).
• Increased glucocorticoid receptor (GR) expression and activity are implicated as a resistance mechanism in CRPC.
• The link between GR activity and downstream signaling pathways in AR-inhibited CRPC requires further elucidation.

Purpose of the Study:

• To investigate the association between GR transcriptional activity and cyclic adenosine monophosphate (cAMP)-associated gene expression in CRPC under ARSi.
• To evaluate the therapeutic potential of selective GR modulators (SGRMs) in combination with AR antagonists for CRPC treatment.

Main Methods:

• Analysis of GR-mediated gene expression in CRPC models and patient samples.
• Assessment of cAMP signaling pathway activation, including protein kinase inhibitor beta (PKIB) and protein kinase A (PKA) activity.
• In vivo studies using CRPC xenograft models treated with enzalutamide and SGRMs.
• Correlation analysis of GR activity and cAMP pathway gene expression in patient-derived xenografts and metastatic CRPC samples.

Main Results:

• GR activation under ARSi upregulates cAMP-associated gene expression, including PKIB, leading to increased PKA activity.
• Combination therapy with enzalutamide and SGRMs delayed CRPC progression in mice and reduced tumor PKIB mRNA levels.
• Metastatic CRPC samples and patient-derived xenografts show enrichment of cAMP pathway signaling and high GR activity.

Conclusions:

• GR transcriptional activity promotes cAMP signaling in AR-antagonized CRPC, representing a novel oncogenic mechanism.
• Targeting GR with SGRMs in combination with AR antagonists may offer a therapeutic strategy to delay CRPC recurrence by inhibiting tumor cAMP/PKA pathways.