Figure 10. Proposed pathways of cell death induced in cancer cells by inhibition of Cdc7 kinase.

Inhibition of initiation of DNA replication by suppression of Cdc7 kinase leads to activation of ATM/ATR, which may result in the activation of three checkpoint kinases, Chk1, MK2, and Chk2. Since Cdc7 is actively required for activation of Chk1 [19], [46], Chk1 is not activated under this condition. Activated MK2 may phosphorylate Cdc2/Cyclin B1, which in turn may be recognized and bound by 14-3-3σ protein and is sequestered in cytoplasm. Cdc7 depletion can induce DNA damages in cancer cells [19] and activated Chk2 would stabilize the FoxM1 transcription factor, which would induce the expression of CyclinB1 [47]. The accumulated CyclinB1 protein is abruptly transported into nuclei and mitotic catastrophe or post-mitotic cell death is induced. In p53-positive cancer cells, p53, activated through ATM/ATR, would induce G1 delay as well as S phase delay possibly through induction of p21. p53 inhibits transcription of FoxM1 [37], [38], thus preventing the induction of Cyclin B1. However, aberrant S phase progression in the absence of Cdc7 would induce cell death in p53-positive cancer cells.