Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang, South Korea.
Department of Urology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea.
J Exp Clin Cancer Res. 2019 Aug 6;38(1):342. doi: 10.1186/s13046-019-1342-5.
Androgen receptor (AR)-targeted treatments improve the survival of castration-resistant prostate cancer (CRPC) patients; however, secondary resistance to these agents ultimately occurs in virtually all patients. Therefore, alternative therapeutic targets are urgently needed. Since growing evidence demonstrates that WNT/β-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule β-catenin inhibitor, were investigated in prostate cancer.
We assessed the antitumor activity of CWP232291 in prostate cancer cell lines and primary cells derived from CRPC patients. The effect of CWP232291 on apoptotic cell death, endoplasmic reticulum (ER) stress, cell viability, and WNT/β-catenin signaling was evaluated by flow cytometry, western blotting, luciferase reporter assay, and fluorescence microscopy. Antitumor efficacy was assessed in two CRPC xenograft mouse models.
CWP232291 induced ER stress, resulting in upregulation of the proapoptotic protein CHOP and activation of caspase-3-dependent apoptosis. In addition, CWP232291 suppressed the expression of β-catenin by affecting WNT-dependent transcriptional activity, and downregulated AR and its splice variants in prostate cancer cells. Antitumor activity was observed in prostate cancer cells in vitro and ex vivo, and antitumor efficacy was observed in vivo.
Beyond providing preclinical evidence of therapeutic efficacy for the novel small molecule β-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/β-catenin signaling may be a novel strategy against CRPC.
雄激素受体（AR）靶向治疗可改善去势抵抗性前列腺癌（CRPC）患者的生存率；然而，这些药物的继发性耐药最终几乎会出现在所有患者中。因此，迫切需要替代的治疗靶点。由于越来越多的证据表明 WNT/β-连环蛋白信号在 CRPC 中发挥重要作用，因此研究了小分子β-连环蛋白抑制剂 CWP232291 对前列腺癌的抗肿瘤活性和作用机制。
我们评估了 CWP232291 在前列腺癌细胞系和源自 CRPC 患者的原代细胞中的抗肿瘤活性。通过流式细胞术、Western blot、荧光素酶报告基因检测和荧光显微镜评估 CWP232291 对细胞凋亡、内质网（ER）应激、细胞活力和 WNT/β-连环蛋白信号的影响。在两种 CRPC 异种移植小鼠模型中评估抗肿瘤疗效。
CWP232291 诱导 ER 应激，导致促凋亡蛋白 CHOP 上调和 caspase-3 依赖性细胞凋亡激活。此外，CWP232291 通过影响 WNT 依赖性转录活性抑制β-连环蛋白的表达，并下调前列腺癌细胞中的 AR 及其剪接变体。在体外和原代细胞中观察到前列腺癌细胞的抗肿瘤活性，并在体内观察到抗肿瘤疗效。
除了为新型小分子β-连环蛋白抑制剂 CWP232291 在 CRPC 中的治疗效果提供临床前证据外，我们的结果表明，诱导 ER 应激和靶向 WNT/β-连环蛋白信号可能是对抗 CRPC 的一种新策略。
