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p12(CDK2-AP1) mediates DNA damage responses induced by cisplatin
Yong Kim1, Jim McBride, Rong Zhang
1School of Dentistry and Dental Research Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Oncogene
|November 16, 2004
Summary
p12(CDK2-AP1) deficiency enhances DNA repair and confers resistance to cisplatin chemotherapy. This suggests p12(CDK2-AP1) modulation could improve oral cancer treatment outcomes.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Therapeutics
Background:
- Cisplatin is a cornerstone chemotherapy agent for various cancers, including oral and head and neck cancers.
- Understanding cellular mechanisms of cisplatin resistance is crucial for improving treatment efficacy.
- The role of p12(CDK2-AP1) in cellular responses to DNA-damaging agents like cisplatin remains largely unexplored.
Purpose of the Study:
- To investigate the biological function of p12(CDK2-AP1) in cellular responses to cisplatin treatment.
- To determine if p12(CDK2-AP1) influences DNA repair, apoptosis, and cell cycle progression following cisplatin exposure.
- To evaluate the therapeutic potential of targeting p12(CDK2-AP1) in oral/head and neck cancers.
Main Methods:
- Generation of murine ES p12(CDK2-AP1) knockout clones via targeted gene disruption.
- Assessment of cellular proliferation, cell cycle distribution (S and G2/M phases), DNA repair activity (host cell reactivation assay), and apoptosis.
- Validation using stable p12(CDK2-AP1) short interfering RNA (siRNA) clones in human oral keratinocytes and measurement of CDK2 kinase activity.
Main Results:
- p12(CDK2-AP1) knockout clones exhibited increased proliferation, elevated S-phase, and reduced G2/M populations.
- These knockout clones demonstrated resistance to cisplatin, enhanced DNA repair, and significantly reduced apoptosis.
- Downregulation of p12(CDK2-AP1) in human cells confirmed cisplatin resistance, and sustained CDK2 kinase activity was observed in knockout cells post-cisplatin treatment.
Conclusions:
- p12(CDK2-AP1) plays a significant role in mediating cellular responses to cisplatin, primarily by modulating CDK2 kinase activity.
- Loss of p12(CDK2-AP1) confers resistance to cisplatin through enhanced DNA repair and reduced apoptosis.
- p12(CDK2-AP1) represents a potential gene therapeutic target for oral/head and neck cancers when combined with DNA-damaging agents like cisplatin.