Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression.
We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra-O-methyl nordihydroguaiaretic acid (M(4)N) and that M(4)N is likely responsible for causing growth arrest in M(4)N-treated transformed C3 cells. Here, we show that after M(4)N treatment and cell-cycle arrest, expression of the Sp1-dependent survivin gene, a member of the inhibitor of apoptosis family, is also suppressed, and the mitochondrial apoptotic pathway is activated. To confirm that inhibition of Cdc2 and survivin gene expression is necessary for M(4)N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M(4)N-treated cells. Cell division was transiently restored in the presence of M(4)N after transfection of an exogenous Cdc2 gene copy under the control of the Sp1-independent cytomegalovirus promoter. Caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. The results suggest that M(4)N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.
Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA.
Chih-Chuan
CC
Chang
Jonathan D
JD
Heller
Jennifer
J
Kuo
Ru Chih C
RC
Huang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D019926:Cyclin B / Q000032:analysis; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D051034:Inhibitor of Apoptosis Proteins; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009363:Neoplasm Proteins; D000077022:Survivin
C107489:BIRC5 protein, human; D019926:Cyclin B; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C076852:terameprocol; D009637:Masoprocol; D016203:CDC2 Protein Kinase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases