Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Lei, Ming; Erikson, Raymond L.

doi:10.1038/onc.2008.36

Cited by 40 publications

(30 citation statements)

References 28 publications

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“…Alternatively, depletion of Plk1 by small-interfering RNA is not able to totally knock out Plk1 and the remaining Plk1 may not be sufficient for survival of Plk1-addicted cancer cells, but for normal cells. This is in accordance with a recent report 49 that sensitivity of normal cells to Plk1 depletion is dependent on the depletion level. However, an interesting review by Lens et al 50 suggests that it is unlikely to have Plk1-addicted cells, and the contribution of Plk1 to tumor formation might be largely due to the induction of chromosome instability.…”

Section: Discussionsupporting

confidence: 82%

Polo-Box Domain Inhibitor Poloxin Activates the Spindle Assembly Checkpoint and Inhibits Tumor Growth in Vivo

Yuan

Sanhaji

Krämer

et al. 2011

The American Journal of Pathology

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Polo-like kinase 1 (Plk1) is widely established as one of the most promising targets in oncology. Although the protein kinase domain of Plk1 is highly conserved, the polo-box domain (PBD) of Plk1 provides a much more compelling site to specifically inhibit the localization and target binding of Plk1. We recently identified, via fluorescence polarization assay, the natural product derivative, Poloxin, as the first smallmolecule inhibitor specifically targeting the function of the Plk1 PBD. In this study, we characterized its mitotic phenotype and its function in vitro and in vivo. Poloxin induces centrosome fragmentation and abnormal spindle and chromosome misalignment, which activate the spindle assembly checkpoint and prolong mitosis. Notably, centrosomal fragmentation induced by Poloxin is partially attributable to dysfunctional Kizuna, a key substrate of Plk1 at centrosomes. Moreover, Poloxin strongly inhibits proliferation of a panel of cancer cells by inducing mitotic arrest, followed by a surge of apoptosis. More important, we report, for the first time to our knowledge, that the PBD inhibitor, Poloxin, significantly suppresses tumor growth of cancer cell lines in xenograft mouse models by lowering the proliferation rate and triggering apoptosis in treated tumor tissues. The data highlight that targeting the PBD by Poloxin is a powerful approach for selectively inhibiting Plk1 function in vitro and in vivo.

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Section: Discussionsupporting

confidence: 82%

Polo-Box Domain Inhibitor Poloxin Activates the Spindle Assembly Checkpoint and Inhibits Tumor Growth in Vivo

Yuan

Sanhaji

Krämer

et al. 2011

The American Journal of Pathology

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“…In the face of chemotherapy-induced DNA damage and disordered cell replication, LB-1.2 up-regulates Akt-1, which has the potential to stimulate cell growth, and, at the same time, interferes with p53-mediated cell cycle arrest by stabilizing MDM2 (27). An increase in pAkt-1 activates Plk-1, interfering with activation of a checkpoint at G2/M (5,8) and activating TCTP by phosphorylation (21). Phosphorylation of TCTP decreases the stabilization of microtubules (22,23), which may contribute to the development of mitotic catastrophe after exposure of cancer cells to LB-1.2.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Lü

Kovach

Johnson

et al. 2009

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

147

168

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A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

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“…Studies conducted at different time points during the progression from oocyte to embryo suggest that RSK1 and Plk1 share a close relationship. RSK1 inhibits the effects of Plk1-Myt1 interactions, and previous studies indicate that MEK1/2 and ERK1/2 are phosphorylated in Plk1-depleted cells (28); however, it is still not clear whether Plk1 interacts with RSK1 and/or how this pathway operates.…”

mentioning

confidence: 97%

Involvement of Polo-like Kinase 1 (Plk1) in Mitotic Arrest by Inhibition of Mitogen-activated Protein Kinase-Extracellular Signal-regulated Kinase-Ribosomal S6 Kinase 1 (MEK-ERK-RSK1) Cascade

Chen

Zhou

et al. 2012

Journal of Biological Chemistry

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Background: Plk1 can be inhibited by RSK1 during meiosis. Results: Activities of members of the MEK-ERK-RSK1 signaling pathway increase when Plk1 is knocked down, and both of these pathways shut down during cell cycle arrest. Conclusion: Plk1 inhibits the activity of RSK1 via a feedback signal transduction mode during mitosis. Significance: We show that Plk1 is involved in G 2 /M transition by inhibiting the RSK1 pathway.

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Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Cited by 40 publications

References 28 publications

Polo-Box Domain Inhibitor Poloxin Activates the Spindle Assembly Checkpoint and Inhibits Tumor Growth in Vivo

Polo-Box Domain Inhibitor Poloxin Activates the Spindle Assembly Checkpoint and Inhibits Tumor Growth in Vivo

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Involvement of Polo-like Kinase 1 (Plk1) in Mitotic Arrest by Inhibition of Mitogen-activated Protein Kinase-Extracellular Signal-regulated Kinase-Ribosomal S6 Kinase 1 (MEK-ERK-RSK1) Cascade

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