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Protection of cisplatin cytotoxicity by an inactive cyclin-dependent kinase

Rawad Hodeify1, Judit Megyesi, Adel Tarcsafalvi

  • 1Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

American Journal of Physiology. Renal Physiology
|May 7, 2010
PubMed

Insights

Cisplatin

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Cisplatin is a widely used chemotherapy drug.
  • Cisplatin's effectiveness is limited by resistance mechanisms.
  • Cyclin-dependent kinase 2 (Cdk2) plays a role in cisplatin-induced cell death.

Purpose of the Study:

  • To investigate the role of Cdk2 in cisplatin cytotoxicity.
  • To determine if a kinase-inactive Cdk2 mutant can protect against cisplatin.
  • To elucidate the pathways of cisplatin-induced cell death mediated by Cdk2.

Main Methods:

  • Design and expression of a kinase-inactive Cdk2 mutant (Cdk2-F80G) in mouse kidney cells.
  • Co-expression of the mutant with cyclin A to activate it.
  • Assessment of cell viability, apoptosis, endonuclease G release, cytochrome c release, and caspase-3 activation following cisplatin treatment.

Main Results:

  • The inactive Cdk2 mutant protected cells from cisplatin-induced cytotoxicity.
  • Activation of the mutant by cyclin A led to nuclear localization and loss of protection.
  • Activated mutant cells exhibited apoptosis with endonuclease G release but not cytochrome c release or significant caspase-3 activation.
  • Cisplatin appears to induce both caspase-dependent and -independent cell death pathways.

Conclusions:

  • Cdk2 is essential for both caspase-dependent and -independent cell death pathways induced by cisplatin.
  • The inactive Cdk2 mutant can block both pathways, preventing cisplatin-induced apoptosis.
  • Activation of the Cdk2 mutant preferentially leads to caspase-independent cell death.

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