Cell type–dependent effects of Polo-like kinase 1 inhibition compared with targeted polo box interference in cancer cell lines

Fink, Jenny; Sanders, Karl; Rippl, Alexandra; Finkernagel, Sylvia; Beckers, Thomas; Schmidt, Mathias

doi:10.1158/1535-7163.mct-07-0048

Cited by 13 publications

(8 citation statements)

References 39 publications

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“…This residue is a direct target of AurkB (27, 28), and as shown in Figure 3A, the Aurk inhibitor VX-680 potently blocked its phosphorylation. Paradoxically, inhibitors of Plk1 have been reported to promote increased phosphorylation of Histone 3 on Serine 10 (29, 30); consistent with this, we observed increased levels of phospho-H3 Ser10 and decreased levels of Serine 46 phosphorylation of TCTP (translationally controlled tumor protein, a direct Plk1 substrate) upon treatment with BI-2536 (Figure 3B and data not shown). These data suggest that inhibitors of Aurora and Polo-like kinases are active in patched mutant tumor cells.…”

Section: Resultssupporting

confidence: 87%

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

et al. 2013

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Medulloblastoma (MB) is the most common malignant brain tumor in children. While aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the Sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated MBs do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated MB. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPCs). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent MB. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2/M phases of the cell cycle. Here, we show that CD15+ cells progress more rapidly through the cell cycle than CD15- cells and contain an increased proportion of cells in G2/M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora and Polo-like kinases, key regulators of G2/M, induces cell cycle arrest, apoptosis and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived MB xenografts are also sensitive to Aurora and Polo-like kinase inhibitors. Our findings suggest that targeting G2/M regulators may represent a novel approach for treatment of human MB.

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Section: Resultssupporting

confidence: 87%

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

et al. 2013

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“…In contrast to our results, Liu and Erikson suggested that PLK1 depletion increases Cdc2/cyclin B complex activity in HeLa cells (28). However, Fink et al showed that inhibition of PLK1 activity exerts contrary effects depending on cell type (29). Current studies in our laboratory are underway to explore the signaling pathway modulated by PLK1 in oral cancer cells.…”

Section: Discussioncontrasting

confidence: 99%

The antitumor effect of PLK1 and HSF1 double knockdown on human oral carcinoma cells

Kim

Kwon²,

Yoon³

et al. 2010

Int J Oncol

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Abstract. High levels of mitotic progression-associated PLK1 and stress-associated HSF1 have been observed in various human cancers. In the present study, we investigated the effects of PLK1 and HSF1 knockdown on the proliferation of oral cancer cells using small interfering RNA. In human oral squamous cell carcinoma (SCC) tissues, the levels of PLK1 and HSF1 were higher compared to normal tissues. The expression levels of PLK1 and HSF1 were also elevated in the human oral SCC cell lines FaDu and HEp-2. Disruption of PLK1 induced cell cycle arrest at G2/M phase as well as apoptosis in oral cancer cells. Interestingly, knockdown of both PLK1 and HSF1 expression decreased cell proliferation while increasing apoptotic cell death in synergistic fashion. These results establish the potential value of PLK1 and HSF1 as targets for oral cancer therapy.

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“…The predicted human PLK5 is also efficient in inducing G 1 arrest (Fig. 1B), whereas overexpression of the PBD region of Plk1, Plk2, or Plk3 (constructs similar to Plk5-⌬N or PLK5) results in no or minor differences in G 1 arrest (17,22,24) (see Fig. S3 in the supplemental material).…”

Section: Plk5 Is An Antiproliferative Plk Family Member the Murinementioning

confidence: 96%

Plk5, a Polo Box Domain-Only Protein with Specific Roles in Neuron Differentiation and Glioblastoma Suppression

Cárcer

Escobar

Higuero

et al. 2011

Molecular and Cellular Biology

102

104

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Polo-like kinases (Plks) are characterized by the presence of a specific domain, known as the polo box (PBD), involved in protein-protein interactions. Plk1 to Plk4 are involved in centrosome biology as well as the regulation of mitosis, cytokinesis, and cell cycle checkpoints in response to genotoxic stress. We have analyzed here the new member of the vertebrate family, Plk5, a protein that lacks the kinase domain in humans. Plk5 does not seem to have a role in cell cycle progression; in fact, it is downregulated in proliferating cells and accumulates in quiescent cells. This protein is mostly expressed in the brain of both mice and humans, and it modulates the formation of neuritic processes upon stimulation of the brain-derived neurotrophic factor (BDNF)/nerve growth factor (NGF)-Ras pathway in neurons. The human PLK5 gene is significantly silenced in astrocytoma and glioblastoma multiforme by promoter hypermethylation, suggesting a tumor suppressor function for this gene. Indeed, overexpression of Plk5 has potent apoptotic effects in these tumor cells. Thus, Plk5 seems to have evolved as a kinase-deficient PBD-containing protein with nervous system-specific functions and tumor suppressor activity in brain cancer.

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Cell type–dependent effects of Polo-like kinase 1 inhibition compared with targeted polo box interference in cancer cell lines

Cited by 13 publications

References 39 publications

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

The antitumor effect of PLK1 and HSF1 double knockdown on human oral carcinoma cells

Plk5, a Polo Box Domain-Only Protein with Specific Roles in Neuron Differentiation and Glioblastoma Suppression

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