Gemcitabine-Induced Activation of Checkpoint Signaling Pathways That Affect Tumor Cell Survival
| Autor: | Kevin M. Hopkins, Jennifer S. Hackbarth, Howard B. Lieberman, Junjie Chen, Yong Un Baek, Sonnet J.H. Arlander, Karen S. Flatten, Jill M. Wagner, Scott H. Kaufmann, M. Bijoy Thomas, David A. Loegering, Benjamin T. Vroman, William A. Cliby, Larry M. Karnitz |
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| Rok vydání: | 2005 |
| Předmět: |
Cell Survival
DNA damage DNA repair Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Deoxycytidine Cell Line Tumor Humans CHEK1 Checkpoint Kinase 2 Pharmacology Dose-Response Relationship Drug Kinase Tumor Suppressor Proteins Cytarabine DNA replication G2-M DNA damage checkpoint Gemcitabine Cell biology DNA-Binding Proteins Checkpoint Kinase 1 Molecular Medicine biological phenomena cell phenomena and immunity Protein Kinases Signal Transduction |
| Zdroj: | Molecular Pharmacology. 68:1636-1644 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.105.012716 |
| Popis: | Two signaling pathways are activated by antineoplastic therapies that damage DNA and stall replication. In one pathway, double-strand breaks activate ataxia-telangiectasia mutated kinase (ATM) and checkpoint kinase 2 (Chk2), two protein kinases that regulate apoptosis, cell-cycle arrest, and DNA repair. In the second pathway, other types of DNA lesions and replication stress activate the Rad9-Hus1-Rad1 complex and the protein kinases ataxia-telangiectasia mutated and Rad3-related kinase (ATR) and checkpoint kinase 1 (Chk1), leading to changes that block cell-cycle progression, stabilize stalled replication forks, and influence DNA repair. Gemcitabine and cytarabine are two highly active chemotherapeutic agents that disrupt DNA replication. Here, we examine the roles these pathways play in tumor cell survival after treatment with these agents. Cells lacking Rad9, Chk1, or ATR were more sensitive to gemcitabine and cytarabine, consistent with the fact that these agents stall replication forks, and this sensitization was independent of p53 status. Interestingly, ATM depletion sensitized cells to gemcitabine and ionizing radiation but not cytarabine. Together, these results demonstrate that 1) gemcitabine triggers both checkpoint signaling pathways, 2) both pathways contribute to cell survival after gemcitabine-induced replication stress, and 3) although gemcitabine and cytarabine both stall replication forks, ATM plays differential roles in cell survival after treatment with these agents. |
| Databáze: | OpenAIRE |
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