Targeted depletion of Polo-like kinase (Plk) 1 through lentiviral shRNA or a small-molecule inhibitor causes mitotic catastrophe and induction of apoptosis in human melanoma cells.
Targeted depletion of Polo-like kinase (Plk) 1 through lentiviral shRNA or a small-molecule inhibitor causes mitotic catastrophe and induction of apoptosis in human melanoma cells.
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DOI：
10.1038/jid.2009.172
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发表时间：
2009-12
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黑色素瘤是最致命的皮肤癌之一，对目前可用的治疗方法仍有抗药性。因此，需要新的机制和基于靶点的方法来治疗这种肿瘤。Polo样激酶1（Plk 1）已被证明是有丝分裂进入，进展和退出的关键调节因子。Plk 1升高与几种癌症类型的侵袭性以及疾病预后不良有关。然而，Plk 1在黑色素瘤中的作用还没有得到很好的确定。在这里，我们证明，Plk 1是过度表达的临床组织标本和培养的人黑色素瘤细胞（WM 115，A375和HS 294 T）相比，正常皮肤组织和培养的正常黑色素细胞，分别。此外，通过Plk 1特异性shRNA敲低Plk 1基因或通过小分子抑制剂抑制其活性导致黑色素瘤细胞的活力和生长显著降低，而不影响正常人黑色素细胞。此外，Plk 1抑制导致黑色素瘤细胞的显著i）克隆形成存活减少，ii）多个有丝分裂错误，iii）G2/M细胞周期停滞，和iv）细胞凋亡。这项研究表明Plk 1可能与黑色素瘤的发生和/或进展具有功能相关性。我们认为靶向Plk 1可能是治疗黑色素瘤的一种可行方法。
Melanoma, one of the most lethal forms of skin cancer, remains resistant to currently available treatments. Therefore, novel mechanism and target-based approaches are needed for the management of this neoplasm. Polo-like kinase 1 (Plk1) has been shown to be a crucial regulator of mitotic entry, progression and exit. Elevated Plk1 has been associated with aggressiveness of several cancer types as well as with poor disease prognosis. However, the role of Plk1 in melanoma is not well-established. Here, we demonstrate that Plk1 is over-expressed in both clinical tissue specimens and cultured human melanoma cells (WM115, A375 and HS294T) when compared to normal skin tissues and cultured normal melanocytes, respectively. Further, Plk1 gene knockdown via Plk1 specific shRNA or its activity inhibition by a small molecule inhibitor resulted in a significant decrease in the viability and growth of melanoma cells without affecting normal human melanocytes. In addition, Plk1 inhibition resulted in a significant i) decrease in clonogenic survival, ii) multiple mitotic errors, iii) G2/M cell cycle arrest, and iv) apoptosis of melanoma cells. This study suggests Plk1 may have a functional relevance towards melanoma development and/or progression. We suggest that targeting of Plk1 may be a viable approach for the treatment of melanoma.