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Inhibition of cisplatin-induced ATR activity and enhanced sensitivity to cisplatin
Eugenia M Yazlovitskaya1, Diane L Persons
1Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Abstract:
Ataxia teleangiectasia mutated (ATM) kinase, ATM-Rad3-related (ATR) kinase and DNA-protein kinase (DNA-PK) belong to a subgroup of protein kinases which play a role in the DNA damage response. In this study, cisplatin was shown to increase ATR activity and decrease ATM and DNA-PK activity. Caffeine, a nonspecific inhibitor of ATR, enhanced the cytotoxic effect of cisplatin, modestly decreased the p53 and p21WAF-1 response to cisplatin, and affected the cdc2-p34/cyclin B1 complex by decreasing both cyclin B1 protein accumulation and cdc2-p34 tyrosine 15 phosphorylation. The observed alteration of several potential ATR downstream targets suggests that inhibition of ATR activity may be one of the mechanism by which caffeine regulates sensitivity to cisplatin.
Insights
Cisplatin affects DNA damage response kinases, increasing ATR activity. Caffeine enhances cisplatin
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Ataxia teleangiectasia mutated (ATM) kinase, ATM-Rad3-related (ATR) kinase, and DNA-protein kinase (DNA-PK) are key regulators of the DNA damage response.
- Understanding how these kinases are modulated by chemotherapeutic agents is crucial for improving cancer treatment.
Purpose of the Study:
- To investigate the effects of cisplatin on ATM, ATR, and DNA-PK activities.
- To explore the role of ATR inhibition by caffeine in modulating cisplatin's cytotoxic effects and downstream signaling pathways.
Main Methods:
- Assessing kinase activities (ATM, ATR, DNA-PK) following cisplatin treatment.
- Evaluating the impact of caffeine, an ATR inhibitor, on cisplatin cytotoxicity.
- Analyzing the modulation of key proteins (p53, p21WAF-1, cdc2-p34/cyclin B1 complex) in response to cisplatin and caffeine.
Main Results:
- Cisplatin increased ATR activity while decreasing ATM and DNA-PK activity.
- Caffeine enhanced the cytotoxic effect of cisplatin.
- Caffeine treatment led to decreased p53 and p21WAF-1 response and altered the cdc2-p34/cyclin B1 complex.
Conclusions:
- ATR kinase activity is modulated by cisplatin.
- Inhibition of ATR activity by caffeine may be a mechanism underlying caffeine's regulation of cisplatin sensitivity.
- Targeting ATR could be a strategy to enhance chemotherapy efficacy.
