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Received for publication March 10, 2005.
Revised July 26, 2005.
Accepted for publication August 26, 2005.
Two signaling pathways are activated by antineoplastic therapies that damage DNA and stall replication. In one pathway, double-strand breaks activate ATM and 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 (9-1-1) complex and the protein kinases ATR and 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 following 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. Collectively, these results demonstrate that (1) gemcitabine triggers both checkpoint signaling pathways, (2) both pathways contribute to cell survival following 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.
Key words:
Mechanisms of cell killing/apoptosis, Nucleoside/Nucleotide derivatives
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