Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression.
نویسندگان
چکیده
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.
منابع مشابه
Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo.
The transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) was found to arrest the proliferation of C3, C33a, CEM-T4, and TC-1 cells in culture at the G2 stage of the cell cycle. Investigation into the mechanism of arrest revealed that M4N reduces mRNA levels and subsequent protein production of the cyclin-dependent kinase CDC2, resulting in the inactivation of the CDC2/cyclin B...
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ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 101 36 شماره
صفحات -
تاریخ انتشار 2004