Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
Department of Physiology, School of Medicine, University of Jeddah, Jeddah 21589, Saudi Arabia.
Int J Mol Sci. 2023 Apr 12;24(8):7130. doi: 10.3390/ijms24087130.
Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, β-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. β-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that β-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active β-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and β-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and β-catenin, using the GR modulator CORT-108297 and the selective β-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24- cell populations in tumorspheres. These results indicate that GR and β-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance.
治疗抵抗阻碍了晚期前列腺癌 (PCa) 患者对抗雄激素治疗和紫杉烷类化疗的疗效。糖皮质激素受体 (GR) 信号转导介导了对雄激素受体信号抑制剂 (ARSI) 的抵抗，并且最近也与 PCa 对多西紫杉醇 (DTX) 的耐药性有关，这表明它在治疗交叉耐药中起作用。与 GR 一样，β-连环蛋白在转移性和治疗耐药性肿瘤中上调，并且是癌症干性和 ARSI 耐药性的关键调节剂。β-连环蛋白与 AR 相互作用以促进 PCa 的进展。鉴于 AR 和 GR 之间的结构和功能相似性，我们假设β-连环蛋白也与 GR 相互作用以影响 PCa 干性和化学抗性。正如预期的那样，我们观察到用糖皮质激素地塞米松治疗可促进 PCa 细胞中 GR 和活性β-连环蛋白的核积累。共免疫沉淀研究表明，GR 和β-连环蛋白在 DTX 耐药和 DTX 敏感的 PCa 细胞中相互作用。用 GR 调节剂 CORT-108297 和选择性β-连环蛋白抑制剂 MSAB 联合抑制 GR 和β-连环蛋白，可增强在贴壁和球体培养物中生长的 DTX 耐药性 PCa 细胞的细胞毒性，并减少肿瘤球体中的 CD44+/CD24-细胞群。这些结果表明，GR 和β-连环蛋白影响 DTX 耐药细胞的细胞存活、干性和肿瘤球体形成。它们的联合抑制可能是克服 PCa 治疗交叉耐药的一种有前途的治疗策略。
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