Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
Prostate. 2022 Jun;82(9):957-969. doi: 10.1002/pros.24342. Epub 2022 Mar 25.
Identification of novel molecular target(s) is important for designing newer mechanistically driven approaches for the treatment of prostate cancer (PCa), which is one of the main causes of morbidity and mortality in men. In this study, we determined the role of polo-like kinase 4 (PLK4), which regulates centriole duplication and centrosome amplification (CA), in PCa.
Employing human PCa tissue microarrays, we assessed the prevalence of CA, correlated with Gleason score, and estimated major causes of CA in PCa (cell doubling vs. centriole overduplication) by staining for mother/mature centrioles. We also assessed PLK4 expression and correlated it with CA in human PCa tissues and cell lines. Further, we determined the effects of PLK4 inhibition in human PCa cells.
Compared to benign prostate, human PCa demonstrated significantly higher CA, which was also positively correlated with the Gleason score. Further, most cases of CA were found to arise by centriole overduplication rather than cell doubling events (e.g., cytokinesis failure) in PCa. In addition, PLK4 was overexpressed in human PCa cell lines and tumors. Moreover, PLK4 inhibitors CFI-400945 and centrinone-B inhibited cell growth, viability, and colony formation of both androgen-responsive and androgen-independent PCa cell lines. PLK4 inhibition also induced cell cycle arrest and senescence in human PCa cells.
CA is prevalent in PCa and arises predominantly by centriole overduplication as opposed to cell doubling events. Loss of centrioles is cellular stress that can promote senescence and suggests that PLK4 inhibition may be a viable therapeutic strategy in PCa.
鉴定新的分子靶标对于设计治疗前列腺癌（PCa）的新型机制驱动方法非常重要，PCa 是男性发病率和死亡率的主要原因之一。在这项研究中，我们确定了调节中心体复制和中心体扩增（CA）的丝氨酸/苏氨酸激酶 polo 样激酶 4（PLK4）在 PCa 中的作用。
我们使用人前列腺癌组织微阵列评估了 CA 的流行率，其与 Gleason 评分相关，并通过对母/成熟中心粒进行染色来估计 PCa 中 CA 的主要原因（细胞加倍与中心粒过度复制）。我们还评估了人 PCa 组织和细胞系中 PLK4 的表达，并将其与 CA 相关联。此外，我们还确定了 PLK4 抑制剂在人 PCa 细胞中的作用。
与良性前列腺相比，人 PCa 表现出明显更高的 CA，其与 Gleason 评分呈正相关。此外，在 PCa 中，大多数 CA 病例是由中心粒过度复制而不是细胞加倍事件（例如，胞质分裂失败）引起的。此外，PLK4 在人前列腺癌细胞系和肿瘤中过度表达。此外，PLK4 抑制剂 CFI-400945 和 centrinone-B 抑制了雄激素反应性和雄激素非依赖性 PCa 细胞系的细胞生长、活力和集落形成。PLK4 抑制也诱导了人 PCa 细胞的细胞周期停滞和衰老。
CA 在 PCa 中很常见，主要由中心粒过度复制引起，而不是细胞加倍事件。中心粒丢失是细胞应激，可以促进衰老，并表明 PLK4 抑制可能是 PCa 的一种可行的治疗策略。
