In castrate-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic “bypass” mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic PC patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs). For example, in the context of ARSi, we found that GR activation resulted in upregulation of protein kinase inhibitor beta (PKIB) mRNA and protein levels, leading to nuclear accumulation of the cAMP-dependent protein kinase A catalytic subunit (PKA-c). Increased PKA-c, in turn, is associated with increased cAMP response element-binding protein (CREB) phosphorylation and activity. Furthermore, enzalutamide and SGRM combination therapy in mice bearing CRPC xenografts delayed CRPC progression compared to enzalutamide therapy alone, and reduced tumor PKIB mRNA expression. Supporting the clinical importance of GR/PKA signaling activation in CRPC, we found a significant enrichment of both cAMP pathway signaling-associated gene expression and high NR3C1 (GR) activity in PDX models and metastatic human CRPC samples. These findings suggest a novel mechanism linking CRPC-induced GR transcriptional activity with increased cAMP signaling in AR-antagonized CRPC. Furthermore, our findings suggest that GR-specific modulation in addition to AR antagonism may delay GR+ CRPC time to recurrence, at least in part, by inhibiting tumor cAMP/PKA pathways.

中文翻译：

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去势抵抗性前列腺癌中糖皮质激素受体 (GR) 激活与 cAMP/PKA 信号传导增强相关

在去势抵抗性前列腺癌（CRPC）中，糖皮质激素受体（GR）表达增加和随之而来的转录活性被认为是响应雄激素受体（AR）信号抑制（ARSi）的致癌“旁路”机制。在此，我们报告 ARSi 后获得的 GR 转录活性与模型系统和转移性 PC 患者样本中环磷酸腺苷 (cAMP) 相关基因表达途径的上调相关。在 ARSi 的背景下，GR 介导的编码 cAMP 信号通路相关蛋白的基因的表达可以通过选择性 GR 调节剂 (SGRM) 的治疗来抑制。例如，在 ARSi 的背景下，我们发现 GR 激活导致蛋白激酶抑制剂 β (PKIB) mRNA 和蛋白水平上调，导致 cAMP 依赖性蛋白激酶 A 催化亚基 (PKA-c) 的核积累。反过来，PKA-c 的增加与 cAMP 反应元件结合蛋白 (CREB) 磷酸化和活性的增加相关。此外，与单独使用恩杂鲁胺治疗相比，恩杂鲁胺和 SGRM 联合治疗携带 CRPC 异种移植物的小鼠可延缓 CRPC 进展，并降低肿瘤 PKIB mRNA 表达。我们发现 PDX 模型和转移性人类 CRPC 样本中 cAMP 通路信号相关基因表达和高 NR3C1 (GR) 活性显着富集，支持了 GR/PKA 信号激活在 CRPC 中的临床重要性。这些发现表明了一种新机制，将 CRPC 诱导的 GR 转录活性与 AR 拮抗的 CRPC 中 cAMP 信号传导增强联系起来。此外，我们的研究结果表明，除了 AR 拮抗作用之外，GR 特异性调节可能至少部分通过抑制肿瘤 cAMP/PKA 途径来延迟 GR+ CRPC 复发时间。