Polo‐like kinase and its inhibitors: Ready for the match to start?

Palmisiano, Neil; Kasner, Margaret

doi:10.1002/ajh.24177

Cited by 21 publications

(13 citation statements)

References 98 publications

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“…Our findings that Atm −/− ;Casp2 −/− lymphoma cells are more resistant to PLK1-I-mediated cell death may have important implications for drug resistance in lymphoma treatment. 47 It is important to note that, while in most dividing cells caspase-2 is inactive, 36 our findings demonstrate that following mitotic stress, a small population of Casp2 −/− cells are resistant to apoptosis and survive as multinucleate and aneuploid cells. Importantly, these cells acquire an ability to survive long term in culture, an attribute likely to contribute to enhanced cellular transformation and tumorigenic potential.…”

Section: Discussionmentioning

confidence: 68%

Caspase-2-mediated cell death is required for deleting aneuploid cells

et al. 2016

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Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2−/−) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2−/− mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.

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Section: Discussionmentioning

confidence: 68%

Caspase-2-mediated cell death is required for deleting aneuploid cells

et al. 2016

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“…Monotreatment phase I/II trials showed limited partial response and stable disease with reduced adverse effects (summary from ref. 73). Subsequent phase I and II trials with combination treatments (such as cisplatin and cytarabine) show improvements in efficacies of response and overall survival for those who responded 85.…”

Section: Plk1 Inhibitors: Role In Chemoradiotherapymentioning

confidence: 99%

“…Multiple phase I/II trials show positive outcomes with partial responses in a few patients and stable disease in several patients (summary from ref. 73). Phase III trial is currently ongoing in patients with myelodysplastic syndrome.…”

Section: Plk1 Inhibitors: Role In Chemoradiotherapymentioning

confidence: 99%

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Molecular interactions of polo-like kinase 1 in human cancers

et al. 2016

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Polo-like kinase 1 (PLK1) is an essential protein in communicating cell-cycle progression and DNA damage. Overexpression of PLK1 has been validated as a marker for poor prognosis in many cancers. PLK1 knockdown decreases the survival of cancer cells. PLK1 is therefore an attractive target for anticancer treatments. Several inhibitors have been developed, and some have been clinically tested to show additive effects with conventional therapies. Upstream regulation of PLK1 involves multiple interactions of proteins such as FoxM1, E2F and p21. Other cancer-related proteins such as pRB and p53 also indirectly influence PLK1 expression. With the high mutation rates of these genes seen in cancers, they may be associated with PLK1 deregulation. This raises the question of whether PLK1 overexpression is a cause or a consequence of oncogenesis. In addition, hypomethylation of the CpG island of the PLK1 promoter region contributes to its upregulation. PLK1 expression can be affected by many factors; thus, it is possible that PLK1 deregulation in each individual patient tumours could be due to different underlying mechanisms.

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“…The expression of PLK1 is variable in both normal and tumour tissues. This had therefore led to the massive development of PLK1 inhibitors, trying to target the PLK1 to improve the treatment outcomes [4] [5] [6] [7]. The development of the drugs was however often halted at Phase I trials, due to inconsistent outcomes and the massive side effects.…”

Section: Introductionmentioning

confidence: 99%

Exploration of Mutation and DNA Methylation of Polo-Like Kinase 1 (PLK1) in Colorectal Cancer

Shin¹,

Wang²,

Lee³

2017

OJPathology

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Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays critical roles in cell cycling and DNA damage response. Overexpression of PLK1 is associated with the poorer prognosis of cancers, including colorectal cancer (CRC). Although the downstream pathways of the overexpression that lead to oncogenesis have been extensively studied, little is known about the factors that cause the overexpression of PLK1 in CRC. DNA methylation was reported to be affecting the expression of PLK1 in some cancers. The study aims to investigate the contribution of genetic mutation and DNA methylation of the PLK1 gene to the overexpression of PLK1 in CRC. The study involves data mining from Catalogue of Somatic Mutations in Cancer (COSMIC) and Uni-ProtKB, Sanger sequencing on DNA from the cell lines HCT116, SW48, Co-lo320DM and T84 to analyse the possible mutation of PLK1. Other than that methylation status of the PLK1 promoter in CRC are also analysed by using mass spectrometry (MS) and pyrosequencing. Data from the COSMIC show the low incidences of PLK1 mutation for CRC (3.02%) with 46 mutations identified. One of the mutation p.R337Q (c.1010G > A) is located in the D-box which is an important motif for protein ubiquitination and eventually proteasomal degradation. Hence this mutation may potentially result in stabilisation of the PLK1 protein. Mutations are detected at the upstream silencer region, the promoter region and Exon1 in HCT116 but are not located at the protein binding or functioning site. Similarly, the same mutation at promoter region is detected in SW48. Differential trends of changes in methylation status of PLK1 in the IR treated CRC cell lines detected by MS reveal the possible association between the methylation and the radiosensitivity. Furthermore, pyrosequencing shows that PLK1 methylation status in tumour tissues with high expression of PLK1 is not significantly different from those with no How to cite this paper: Ng

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Polo‐like kinase and its inhibitors: Ready for the match to start?

Cited by 21 publications

References 98 publications

Caspase-2-mediated cell death is required for deleting aneuploid cells

Caspase-2-mediated cell death is required for deleting aneuploid cells

Molecular interactions of polo-like kinase 1 in human cancers

Exploration of Mutation and DNA Methylation of Polo-Like Kinase 1 (PLK1) in Colorectal Cancer

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