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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1
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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1

Published on: February 25, 2016

Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function

J P Cogswell1, C E Brown, J E Bisi

  • 1Department of Functional Genetics, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA. jpc30240@glaxowellcome.com

Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
|January 10, 2001
PubMed

Insights

Polo-like kinase 1 (PLK1) inhibition causes tumor cell death, not normal cells. This selective cancer cell apoptosis is not due to tumor cells being more dependent on PLK1 for mitotic progression.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Polo-like kinase 1 (PLK1) is crucial for mitosis and a potential cancer therapeutic target.
  • PLK1 initiates the mitotic cascade by activating cdc25C phosphatase.
  • Loss of PLK1 function induces mitotic catastrophe selectively in cancer cells (HeLa) but not normal cells (Hs68).

Purpose of the Study:

  • To investigate if selective mitotic catastrophe induced by PLK1 inhibition extends to other tumor types.
  • To determine if this selectivity is due to tumor-specific dependence on PLK1 for cdc25C activation.

Main Methods:

  • Adenovirus-mediated delivery of a dominant-negative PLK1 gene to block PLK1 function.
  • Comparison of cellular responses (apoptosis, mitotic catastrophe) in various tumor cell lines and normal human mammary epithelial cells.
  • Assessment of cdc25C phosphorylation and cdk1 activation.

Main Results:

  • Dominant-negative PLK1 induced tumor-selective apoptosis in most tested tumor cell lines.
  • Mitotic catastrophe, similar to HeLa cells, occurred in some tumor lines but not in normal human mammary epithelial cells.
  • Normal cells arrested in mitosis but escaped catastrophic events like centrosome maturation loss.
  • PLK1 inhibition blocked cdc25C phosphorylation and cdk1 activation in both tumor and normal cells.

Conclusions:

  • The observed tumor-selective mitotic catastrophe is not caused by a lack of tumor cell dependence on PLK1 for cdc25C activation.
  • PLK1 inhibition represents a promising strategy for selective cancer therapy, inducing apoptosis in tumor cells while sparing normal cells.

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