Abstract:
Polo-like kinase 1 (PLK1) is the principle member of the well conserved serine/threonine kinase family. PLK1 has a key role in the progression of mitosis and recent evidence suggest its important involvement in regulating the G2/M checkpoint, in DNA damage and replication stress response, and in cell death pathways. PLK1 expression is tightly spatially and temporally regulated to ensure its nuclear activation at the late S-phase, until the peak of expression at the G2/M-phase. Recently, new roles of PLK1 have been reported in literature on its implication in the regulation of inflammation and immunological responses. All these biological processes are altered in tumors and, considering that PLK1 is often found overexpressed in several tumor types, its targeting has emerged as a promising anti-cancer therapeutic strategy. In this review, we will summarize the evidence suggesting the role of PLK1 in response to DNA damage, including DNA repair, cell cycle progression, epithelial to mesenchymal transition, cell death pathways and cancer-related immunity. An update of PLK1 inhibitors currently investigated in preclinical and clinical studies, in monotherapy and in combination with existing chemotherapeutic drugs and targeted therapies will be discussed.
摘要:
Polo样激酶1(PLK1)是保守的丝氨酸/苏氨酸激酶家族的主要成员。PLK1在有丝分裂的进展中起关键作用,最近的证据表明其在调节G2/M检查点中的重要参与,在DNA损伤和复制应激反应中,和细胞死亡途径。PLK1的表达在空间和时间上受到严格的调节,以确保其在S期后期的核激活。直到G2/M期的表达峰值。最近,文献报道了PLK1在炎症和免疫反应调节中的新作用。所有这些生物过程在肿瘤中都发生了改变,考虑到PLK1经常在几种肿瘤类型中过度表达,其靶向已成为一种有前途的抗癌治疗策略.在这次审查中,我们将总结表明PLK1在响应DNA损伤中的作用的证据,包括DNA修复,细胞周期进程,上皮向间充质转化,细胞死亡途径和癌症相关免疫。目前在临床前和临床研究中研究的PLK1抑制剂的更新,将讨论单药治疗以及与现有化疗药物和靶向治疗的组合。