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Chair(s): Syljuåsen, Randi
(SY011) Targeting checkpoint kinases to modulate tumor radiosensitivity.
Syljuåsen, Randi*,1, Sørensen, Claus1, Lukas, Jiri1, Bartek, Jiri1, 1 Department of Cell Cycle and Cancer, Institute of Cancer Biology, Copenhagen, Denmark, Denmark
ABSTRACT- Human checkpoint kinase Chk1 has been suggested as a target for cancer treatment. Chk1-inhibition can increase the sensitivity of human cancer cells to the cytotoxic effects of ionizing radiation (IR) or chemotherapeutic drugs, likely due to abrogation of the G2 checkpoint. The present study was initiated to explore the effects of Chk1-inhibition in the presence and absence of IR. We have found that in the presence of IR, Chk1-inhibition efficiently abrogates the S and G2 checkpoints, leading to accelerated onset of mitotic nuclear fragmentation and increased cell death. The formation of nuclear fragmentation in IR-treated human cancer cells was directly visualized by time-lapse videomicroscopy of cells expressing a green fluorescent protein-tagged histone H2B protein. In the absence of IR, Chk1-inhibition causes a rapid and strong phosphorylation of ATR targets in S phase cells, and induces DNA strand breaks. We propose a model where Chk1 is required during normal S phase progression to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. These results may help explain why Chk1 is an essential kinase, and should be taken into account when drugs to inhibit this kinase are considered for use in cancer treatment.
Key words: cell cycle checkpoints, radiosensitivity
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