Department of Genitourinary Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States.
Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, Texas, United States.
Medicine (Baltimore). 2022 Jul 22;101(29):e29716. doi: 10.1097/MD.0000000000029716.
Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor (AR) share overlapping transcriptomes and cistromes. Under enzalutamide treatment, GR signaling can bypass AR activation and promote castration resistance via the expression of a subset of AR-target genes. However, GR-dependent growth under enhanced antiandrogen inhibition occurs only in a subset of primed cells. On the other hand, glucocorticoids have been used successfully in the treatment of prostate cancer for many years. In the context of AR signaling, GR competes with AR for DNA-binding and has the potential to halt the proliferation rate of prostate cancer cells. Their target genes overlap by <50% and they execute unique functions in vivo. In addition, even when AR and GR upregulate the same transcriptional target gene, the effect might not be identical in magnitude. Besides being able to drive tumor proliferation, GR is also a key player in prostate cancer cell survival. Stimulation of GR activity can undermine the effects of enhanced antiandrogen treatment, chemotherapy and radiotherapy. GR activation in prostate cancer can increase prosurvival gene expression. Identifying the full spectrum of GR activity will inform the optimal use of glucocorticosteroids in prostate cancer. It will also determine the best strategies to target the protumorigenic effects of GR.
糖皮质激素通过糖皮质激素受体 (GR) 发挥作用，并在不同类型的癌症中发挥多种作用。在前列腺癌细胞中，GR 和雄激素受体 (AR) 具有重叠的转录组和染色质组。在恩扎鲁胺治疗下，GR 信号可以绕过 AR 激活，并通过表达一组 AR 靶基因促进去势抵抗。然而，在增强的抗雄激素抑制下，仅在一部分已启动的细胞中发生 GR 依赖性生长。另一方面，糖皮质激素多年来已成功用于治疗前列腺癌。在 AR 信号转导的背景下，GR 与 AR 竞争 DNA 结合，并有可能阻止前列腺癌细胞的增殖速度。它们的靶基因重叠不到 50%，并且在体内执行独特的功能。此外，即使 AR 和 GR 上调相同的转录靶基因，其效应在幅度上也可能不完全相同。除了能够驱动肿瘤增殖外，GR 还是前列腺癌细胞存活的关键参与者。GR 活性的刺激会削弱增强的抗雄激素治疗、化疗和放疗的效果。GR 在前列腺癌中的激活可以增加生存相关基因的表达。确定 GR 活性的全貌将为糖皮质激素在前列腺癌中的最佳应用提供信息。它还将确定靶向 GR 促肿瘤作用的最佳策略。
