Sensitization of cancer cells to DNA damage-induced cell death by specific cell cycle G2 checkpoint abrogation.
We devised two short peptides corresponding to amino acids 211-221 of human Cdc25C fused with a part of HIV1-TAT. These peptides inhibited hChk1 and Chk2/HuCds1 kinase activity in vitro and specifically abrogated the G2 checkpoint in vivo. These peptides sensitized p53-defective cancer cell lines to DNA-damaging agent to death without obvious cytotoxic effect on normal cells. Our results clearly indicate that the specific abrogation of the cell cycle G2 checkpoint is a feasible strategy for cancer therapy, and hChk1 and Chk2/HuCds1 are proper targets for that purpose.
Suganuma
M
M
Department of Molecular Genetics, Nagoya City University School of Medicine, Nagoya, Japan.
Kawabe
T
T
Hori
H
H
Funabiki
T
T
Okamoto
T
T
D000595:Amino Acid Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects*; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D016195:G2 Phase; D015696:Gene Products, tat / Q000737:chemistry*; D015497:HIV-1; D006801:Humans; D019169:Jurkat Cells; D010446:Peptide Fragments / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000633:toxicity*; D020687:cdc25 Phosphatases / Q000737:chemistry*; D054322:tat Gene Products, Human Immunodeficiency Virus
D018797:Cell Cycle Proteins; D015696:Gene Products, tat; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D011494:Protein Kinases; C102333:histone H1 kinase; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases