CHK1-regulated S-phase checkpoint response reduces camptothecin cytotoxicity.
The cytotoxicity of camptothecin (CPT) is S phase specific and is associated with an inhibition of DNA replication. The relationship between CPT-induced inhibition of DNA replication and CPT cytotoxicity remains unclear. We previously reported that the CPT-induced inhibition reflects an activated S-phase (S) checkpoint response and that this response is mainly regulated by ATR/CHK1 pathway. In this study, by comparing A1-5 and B4, the two transformed rat embryo fibroblasts cell lines, we showed that with higher CHK1 expression, A1-5 cells had a stronger S checkpoint response and were more resistant to CPT-treatment. The data suggested that over-activated CHK1 in CPT-treated A1-5 cells regulated the strong S checkpoint response through the CDC25A/CDK2 pathway. When the CHK-1 regulated strong S checkpoint response was abolished, A1-5 cells became much more sensitive to CPT-induced killing. These data indicated that CHK1 regulated S checkpoint response protected cells from CPT-induced killing.
Wang
Jia-Lun
JL
Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Wang
Xiang
X
Wang
Hongyan
H
Iliakis
George
G
Wang
Ya
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D002166:Camptothecin / Q000633:toxicity*; D002461:Cell Line, Transformed; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D009841:Oligonucleotides / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D016196:S Phase / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D009841:Oligonucleotides; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D004247:DNA; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat; D002166:Camptothecin