Tetra-O-Methyl Nordihydroguaiaretic Acid Induces Growth Arrest and Cellular Apoptosis by Inhibiting Cdc2 and Survivin Expression

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-09, Vol.101 (36), p.13239-13244
• Main Authors: Chang, Chih-Chuan, Heller, Jonathan D., Kuo, Jennifer, Ru Chih C. Huang, Roseman, Saul
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Biological Sciences; Cancer; Caspase 3; Caspases - metabolism; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - genetics; Cell division; Cell Division - drug effects; Cell growth; Cell Line; Cell lines; Cell nucleus; Cell Nucleus - metabolism; Cellular biology; Cyclin B - analysis; Cyclins; Cytochromes; Cytoplasm - metabolism; Down-Regulation; Epithelial cells; Gene expression; Gene Expression Regulation - drug effects; Inhibitor of Apoptosis Proteins; Masoprocol - analogs & derivatives; Masoprocol - pharmacology; Mice; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - genetics; Neoplasm Proteins; Proteins; Reverse transcriptase polymerase chain reaction; Western blotting
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0405407101

We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra-O-methyl nordihydroguaiaretic acid ( M4 N) and that M4 N is likely responsible for causing growth arrest in M4 N-treated transformed C3 cells. Here, we show that after M4 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 M4 N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M4 N-treated cells. Cell division was transiently restored in the presence of M4 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 M4 N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.