Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival

Larry M. Karnitz, Karen S. Flatten, Jill M. Wagner, David Loegering, Jennifer S. Hackbarth, Sonnet J.H. Arlander, Benjamin T. Vroman, M. Bijoy Thomas, Yong Un Baek, Kevin M. Hopkins, Howard B. Lieberman, Junjie Chen, William A. Cliby, Scott H. Kaufmann

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1636-1644
Number of pages9
JournalMolecular pharmacology
Volume68
Issue number6
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Karnitz, L. M., Flatten, K. S., Wagner, J. M., Loegering, D., Hackbarth, J. S., Arlander, S. J. H., Vroman, B. T., Thomas, M. B., Baek, Y. U., Hopkins, K. M., Lieberman, H. B., Chen, J., Cliby, W. A., & Kaufmann, S. H. (2005). Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Molecular pharmacology, 68(6), 1636-1644. https://doi.org/10.1124/mol.105.012716.