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Divisions of Oncology Research (L.M.K., K.S.F., J.M.W., D.L., B.T.V., Y.-U.B., J.C., S.H.K.) and Gynecologic Surgery (M.B.T., W.A.C.), Mayo Clinic, Rochester, Minnesota; Departments of Molecular Pharmacology and Experimental Therapeutics (L.M.K., S.J.H.A., J.C., S.H.K.) and Biochemistry and Molecular Biology (J.S.H.), Mayo Clinic College of Medicine, Rochester, Minnesota; and Center for Radiological Research, Columbia University, New York, New York (K.M.H., H.B.L.)
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.
Address correspondence to: Dr. Larry M. Karnitz, Division of Oncology Research, Guggenheim 13, Mayo Clinic College of Medicine, 200 First Street, S.W., Rochester, MN 55905. E-mail: Karnitz.Larry{at}Mayo.edu
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