Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers
2010
MDM2is a direct negative regulator of p53. The p53-independent
mdm2-P1 and p53-dependent
mdm2-P2 promoters have been recently shown to harbor Sp1 binding sites. Mithramycin, an inhibitor of Sp1 DNA binding, has been used clinically to treat hypercalcemia and some types of neoplastic disorders. In this study, we investigated the mechanisms behind the anticancer effect of mithramycin. In
gynecologiccancer cells expressing wild-type p53, mithramycin stabilized p53 and increased the expression of the p53 downstream target genes
PUMAand p21, arrested the cell cycle, and induced apoptosis. This activation of the p53 signaling pathway was a specific effect of MTH at concentrations <50 nM. Mithramycin temporally decreased transcription of both the
mdm2-P1 and -P2 promoters. This was followed by a subsequent increase of
mdm2-P2 promoter activity by activated p53. Up-regulated
MDM2was in its active form, and consequently attenuated p53 activity. Although mithramycin activated p53 and suppressed the growth of human
gynecologiccancer cell xenografts in mice, this was accompanied with a secondary up-regulation of
MDM2. Combined treatment with mithramycin and
nutlin-3, a drug that inhibits
MDM2‐p53 interaction, overcame a secondary up-regulation of
MDM2and synergistically inhibited cancer cell growth by inducing apoptosis through activation of the p53 signaling pathway. These observations provide a better understanding of the mechanisms of mithramycin activity, and suggest a potential role for combining mithramycin and
nutlin-3 as a chemotherapeutic treatment for
gynecologiccancers. (Cancer Sci 2010; 101: 1387‐ 1395)
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