Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers

Tatsuhiro Ohgami, Kiyoko Kato, Hiroaki Kobayashi, Kenzo Sonoda, Takafumi Inoue, Shin ichiro Yamaguchi, Tomoko Yoneda, Norio Wake

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Abstract

MDM2 is 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 gynecologic cancer cells expressing wild-type p53, mithramycin stabilized p53 and increased the expression of the p53 downstream target genes PUMA and 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 MDM2 was in its active form, and consequently attenuated p53 activity. Although mithramycin activated p53 and suppressed the growth of human gynecologic cancer 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 MDM2 and 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 gynecologic cancers. (Cancer Sci 2010).

Original languageEnglish
Pages (from-to)1387-1395
Number of pages9
JournalCancer Science
Volume101
Issue number6
DOIs
Publication statusPublished - Jun 1 2010

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Plicamycin
Neoplasms
Up-Regulation
Apoptosis
nutlin 3
Hypercalcemia
Growth
Heterografts
Cell Cycle
Binding Sites

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers. / Ohgami, Tatsuhiro; Kato, Kiyoko; Kobayashi, Hiroaki; Sonoda, Kenzo; Inoue, Takafumi; Yamaguchi, Shin ichiro; Yoneda, Tomoko; Wake, Norio.

In: Cancer Science, Vol. 101, No. 6, 01.06.2010, p. 1387-1395.

Research output: Contribution to journalArticle

Ohgami, Tatsuhiro ; Kato, Kiyoko ; Kobayashi, Hiroaki ; Sonoda, Kenzo ; Inoue, Takafumi ; Yamaguchi, Shin ichiro ; Yoneda, Tomoko ; Wake, Norio. / Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers. In: Cancer Science. 2010 ; Vol. 101, No. 6. pp. 1387-1395.
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