G2-phase arrest through p21(WAF1 / Cip1) induction and cdc2 repression by gnidimacrin in human hepatoma HLE cells.
Gnidimacrin (NSC252940) shows significant antiproliferating activity against human tumor cell lines. This compound binds to and directly activates protein kinase C (PKC). Human hepatoma HLE cells, which lose p53 function and retinoblastoma protein (Rb) expression, are resistant to gnidimacrin. However, PKC betaII gene-transfected HLE (HLE/PKC betaII) cells became sensitive to gnidimacrin, through which cdc2 inhibition and G(2)-phase arrest was caused. p21(WAF1/Cip1) induction and cdc2 reduction were observed and this reduction was abolished through the suppression of p21(WAF1/Cip1) induction by the MEK1/2 inhibitor U0126. Translocation of E2F-4 to the nucleus was also observed in the cells but not in parental HLE cells. Consequently gnidimacrin inhibited cell growth through G(2)-phase arrest not only by the p21(WAF1/Cip1)-dependent suppression of cdc2 activity, but also by subsequent transcriptional suppression of cdc2 itself. In addition, involvement of E2F-4 in cdc2 suppression through a long-lasting induction of p21(WAF1/Cip1) by gnidimacrin is suggested in HLE/PKC betaII cells.
National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Mitsuzi
M
Yoshida
Yuki
Y
Matsui
Akira
A
Iizuka
Yoshinori
Y
Ikarashi
D015153:Blotting, Western; D016203:CDC2 Protein Kinase; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases; D004224:Diterpenes / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C013006:gnidimacrin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases