Targeting Polo-like Kinase in Cancer Therapy

Degenhardt, Yan; Lampkin, Thomas A.

doi:10.1158/1078-0432.ccr-09-1380

Cited by 231 publications

(189 citation statements)

References 68 publications

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“…Therefore, Plk members are attractive drug targets for developing anticancer therapies and are the focus of several small-molecule screens (48)(49)(50). Unlike monomeric Plk1 which autoinhibits and requires multiple external inputs for its activity, Plk4 was not known to autoinhibit but instead was thought to rely on degradation (stimulated by trans-autophosphorylation) as its sole means of regulation.…”

Section: Discussionmentioning

confidence: 99%

Autoinhibition and relief mechanism for Polo-like kinase 4

Klebba

Buster

McLamarrah

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polo-like kinase 4 (Plk4) is a master regulator of centriole duplication, and its hyperactivity induces centriole amplification. Homodimeric Plk4 has been shown to be ubiquitinated as a result of autophosphorylation, thus promoting its own degradation and preventing centriole amplification. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Here, we performed a functional analysis of Plk4's structural domains. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated by a linker (L1) near the kinase domain. Thus, autoinhibition is a conserved feature of Plks. In the case of Plk4, autoinhibition is relieved after homodimerization and is accomplished by PB3 and by autophosphorylation of L1. In contrast, autophosphorylation of the second linker promotes separation of the Plk4 homodimer. Therefore, autoinhibition delays the multiple consequences of activation until Plk4 dimerizes. These findings reveal a complex mechanism of Plk4 regulation and activation which govern the process of centriole duplication.autoinhibition | centriole | centrosome | Polo box | Polo-like kinase 4

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Section: Discussionmentioning

confidence: 99%

Autoinhibition and relief mechanism for Polo-like kinase 4

Klebba

Buster

McLamarrah

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This mitotic kinase controls entry into and progression through mitosis at multiple stages by regulation of centrosome maturation, activation of initiating factors, degradation of inhibitory components, chromosome condensation, and exit from mitosis (reviewed in ref. 8). PLK1 is reported to be overexpressed in numerous cancers including melanoma, prostate, ovarian, colorectal, pancreatic, non-small cell lung, esophageal, endometrial, glioma, squamous cell carcinoma of the head and neck, and non-Hodgkins lymphoma (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

“…PLK1 is reported to be overexpressed in numerous cancers including melanoma, prostate, ovarian, colorectal, pancreatic, non-small cell lung, esophageal, endometrial, glioma, squamous cell carcinoma of the head and neck, and non-Hodgkins lymphoma (reviewed in ref. 8). Moreover, overexpression of PLK1 in DLBCL is linked to poor patient prognosis (9).…”

Section: Introductionmentioning

confidence: 99%

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Shi¹,

Lasky²,

Shinde³

et al. 2012

Molecular Cancer Therapeutics

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Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic. Mol Cancer Ther; 11(9); 2045-53. Ó2012 AACR.

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“…Several RNA interference approaches targeting PLK1 have been investigated and gained certain success in kinds of tumor types. Numerous evidences indicated PLK1 expression level was down-regulated in many tumor types by RNA interference, for instance, breast cancer, stomach cancer, head and neck squamous cell carcinomas, colorectal cancer and a panel of other human cancers [31]. Series of previous studies also suggested knockdown of PLK1 by synthetic siRNA could inhibit cell proliferation, and promote the sensibility of breast cancer cells [15].…”

Section: Discussionmentioning

confidence: 99%

Enhanced chemosensitivity to CPT-11 in colorectal carcinoma xenografts by small hairpin RNA interference targeting PLK1

Fan

Zhang²,

Tian³

et al. 2012

neo

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Commonly used drugs for the treatment of colon cancer patients like CPT-11 shows severe side effects or induces resistance in clinical settings. Thus, we analyzed a combination of PLK1 (polo-like kinase 1)-specific short hair RNA (shRNA), a potent tool to destroy mitosis in cancer cells, together with CPT-11 to enhance drug sensitivity. Cellular proliferation and apoptosis were determined in SW620 colorectal carcinoma cells. Knockdown of cellular PLK1 led to the decreased mRNA and PLK1 protein in RT-PCR and western blot assay. The viability declined (p<0.001) in MTT assay and colony formation assay, and the number of apoptotic cells was clearly increased (p<0.01) in flow cytometric analysis and Hoechst 33258 staining compared with control cells after incubation with PLK1-specific shRNA and SN-38. We found the level of cleaved PARP was also increased in vitro. In vivo, employment of shRNA targeting PLK1 improved the sensitivity to treat SW620 nude mouse model toward CPT-11. The combination therapy inhibited cellular proliferation and promoted apoptosis observed at the percentage of PCNA and caspase3 by immunohistochemistry, accompanied with TUNEL assay. As we expect, the combination treatment delayed tumor growth (p<0.01) and simultaneously reduced tumor weight (p<0.01) compared with control group. Taken together, combination of PLK1-specific shRNA interference with low-dose CPT-11 triggered a antitumor efficacy and represented a potential strategy to treat colon cancer.

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Targeting Polo-like Kinase in Cancer Therapy

Cited by 231 publications

References 68 publications

Autoinhibition and relief mechanism for Polo-like kinase 4

Autoinhibition and relief mechanism for Polo-like kinase 4

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Enhanced chemosensitivity to CPT-11 in colorectal carcinoma xenografts by small hairpin RNA interference targeting PLK1

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