Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment

Liu, Xiaoqi

doi:10.1016/j.tranon.2015.03.010

Cited by 142 publications

(123 citation statements)

References 82 publications

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“…In human somatic cells, inhibited Plk1 leads to multiple mitotic defects, including the formation of abnormal spindles, misaligned chromosomes and i mproper chromosom e condensation [10]. Additionally, up-or downregulation of Plk1 can induce a variety of human tumor cells or mouse embryonic cell mitotic defects, causing aneuploidy or cancer [11][12][13]. This study shows that Plk1 might play a critical role in the process of bipolar spindle assembly and chromosome arrangement during mitosis in somatic cells.…”

Section: Introductionmentioning

confidence: 73%

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

Zhang

Chen

Cui

et al. 2017

J Assist Reprod Genet

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Purpose This study was conducted to examine the dynamic distribution of polo-like 1 kinase (Plk1) and the possible role it plays in first mitotic division during early porcine embryo development. Methods Indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses were used to study the dynamic expression and subcellular localization of Plk1 protein in pig parthenogenetic embryos. Finally, a selective Plk1 inhibitor, GSK461364, was used to evaluate the potential role of Plk1 during this special stage.Results The results showed that Plk1 upon expression exhibited specific dynamic intracellular localization, which closely correlated with the α-tubulin distribution during the first mitotic division. GSK461364 treatment resulted in cleavage failure, with majority of the GSK461364-treated embryos being arrested in prometaphase. Further results of the subcellular structure examination showed that GSK461364 treatment led to a significantly higher proportion of the treated embryos having abnormal spindles and misarranged chromosomes at the prometaphase stage. Conclusions Thus, these results indicated that Plk1 is essential for porcine embryos to complete the first mitotic division. Furthermore, Plk1 regulation was associated with effects on spindle assembly and chromosome arrangement.

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Section: Introductionmentioning

confidence: 73%

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

Zhang

Chen

Cui

et al. 2017

J Assist Reprod Genet

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“…Role of Plk1 in regulation of nonmitotic events. Plk1 is now recognized as a key regulator in cellular processes with diverse functions (11,41). For example, we previously reported that Plk1 phosphorylation of Topors and GTSE1, two negative regulators of the p53 tumor suppressor, leads to p53 inactivation (42,43) and premature termination of cell cycle arrest due to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

Karki

Hodges

et al. 2015

Molecular and Cellular Biology

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The Wnt/␤-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the ␤-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/␤-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear ␤-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/␤-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the ␤-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of ␤-catenin by enhancing binding between glycogen synthase kinase 3␤ (GSK3␤) and ␤-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.

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“…Building off of a sequence similarity to this kinase, as well as an S. Cerivisiae protein involved in the same part of the cell cycle, Cdc5, Golsteyn and colleagues were able to characterize a similar kinase in humans, polo-like kinase 1 (PLK1) (5). Since then, four other members have been added to this family of kinases [reviewed in (6)]. As shown in Figure 1, human Plks 1-4 contain an N terminal kinase domain and vary in the presence of one or more C terminal polo box domains.…”

Section: Introductionmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

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Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor, volasertib, has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed towards understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer.

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Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment

Cited by 142 publications

References 82 publications

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

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