Department of Medicine, Section of Immunology Allergy and Rheumatology, Houston, TX 77030, USA.
Oncogene. 2013 Jun 13;32(24):2973-83. doi: 10.1038/onc.2012.309. Epub 2012 Aug 13.
Castration-resistant prostate cancer (PCa) is refractory to hormone therapy and new strategies for treatment are urgently needed. We found that androgen-insensitive (AI) PCa cells, LNCaP-AI, are reprogrammed to upregulate the mitotic kinase Plk1 (Polo-like kinase 1) and other M-phase cell-cycle proteins, which may underlie AI PCa growth. In androgen-depleted media, LNCaP-AI cells showed exquisite sensitivity to growth inhibition by subnanomolar concentrations of a small molecule inhibitor of Plk1, BI2536, suggesting that these cells are dependent on Plk1 for growth. In contrast, the androgen-responsive parental LNCaP cells showed negligible responses to BI2536 treatment under the same condition. BI2536 treatment of LNCaP-AI cells resulted in an increase in cell death marker PARP-1 (polymerase-1) but did not activate caspase-3, an apoptosis marker, suggesting that the observed cell death was caspase-independent. BI2536-treated LNCaP-AI cells formed multinucleated giant cells that contain clusters of nuclear vesicles indicative of mitotic catastrophe. Live-cell time-lapse imaging revealed that BI2536-treated giant LNCaP-AI cells underwent necroptosis, as evidenced by 'explosive' cell death and partial reversal of cell death by a necroptosis inhibitor. Our studies suggest that LNCaP-AI cells underwent reprogramming in both their cell growth and cell death pathways, rendering them highly sensitive to Plk1 inhibition that induces necroptosis. Harnessing necroptosis through Plk1 inhibition may be explored for therapeutic intervention of castration-resistant PCa.
去势抵抗性前列腺癌（PCa）对激素治疗有抗性，因此急需新的治疗策略。我们发现，雄激素不敏感（AI）PCa 细胞 LNCaP-AI 被重新编程，上调有丝分裂激酶 Plk1（Polo-like kinase 1）和其他 M 期细胞周期蛋白，这可能是 AI PCa 生长的基础。在去雄激素培养基中，LNCaP-AI 细胞对 Plk1 的小分子抑制剂 BI2536 的亚纳摩尔浓度表现出极其敏感的生长抑制作用，这表明这些细胞的生长依赖于 Plk1。相比之下，雄激素反应性亲本 LNCaP 细胞在相同条件下对 BI2536 治疗几乎没有反应。BI2536 处理 LNCaP-AI 细胞导致细胞死亡标志物 PARP-1（多聚酶-1）增加，但不激活凋亡标志物 caspase-3，这表明观察到的细胞死亡是 caspase 非依赖性的。BI2536 处理的 LNCaP-AI 细胞形成多核巨细胞，其中包含核泡簇，提示有丝分裂灾难。活细胞延时成像显示，BI2536 处理的巨 LNCaP-AI 细胞经历了坏死性凋亡，这表现为“爆炸”式细胞死亡和坏死性凋亡抑制剂的部分逆转。我们的研究表明，LNCaP-AI 细胞在其细胞生长和细胞死亡途径中都经历了重编程，使其对诱导坏死性凋亡的 Plk1 抑制高度敏感。通过 Plk1 抑制利用坏死性凋亡可能被探索用于治疗去势抵抗性 PCa。
