PDF(Pubmed)
Abstract：
The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.
摘要：
Polo样激酶1的失调与患有多种人类肿瘤的患者的预后成反比。靶向Polo样激酶1被广泛认为是分子抗癌治疗最有前途的策略之一。虽然临床前结果令人鼓舞，通过显示有限的抗癌活性，临床结果不太令人鼓舞。因此,鉴定负责Polo样激酶1抑制的敏感性的分子和机制是重要的。我们最近表明，p21Cip1/CDKN1A参与有丝分裂的调节，其丢失延长了有丝分裂的持续时间，并伴有各种肿瘤细胞中染色体分离和胞质分裂的缺陷。在本研究中,我们证明p21影响Polo样激酶1抑制剂的疗效，尤其是Poloxin,独特的Polo-box结构域的特异性抑制剂。有趣的是，在用Polo样激酶1抑制剂治疗后，p21在细胞质中增加，与抗凋亡相关，DNA修复和细胞存活。相比之下,p21的缺乏通过显示明显的有丝分裂停滞使肿瘤细胞更容易受到Polo样激酶1的抑制，DNA损伤与细胞凋亡。此外，Plk1抑制剂的长期治疗可强烈诱导具有功能性p21的肿瘤细胞的衰老状态。我们建议p21状态可能是预测Plk1抑制功效的有用生物标志物。
