An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer

Shin Suga, Kiyoko Kato, Tatsuhiro Ohgami, Asako Yamayoshi, Sawako Adachi, Kazuo Asanoma, Shinichiro Yamaguchi, Takahiro Arima, Katsuyuki Kinoshita, Norio Wake

研究成果: Contribution to journalArticle査読

38 被引用数 (Scopus)

抄録

Objective.: We previously demonstrated that that the Ras/ER/MDM2 pathway was critical for NIH3T3 cell transformation. In this study, we examined the effect of blocking this pathway on cell growth in gynecologic cancer cells. Methods.: (1) The levels of MDM2, ER, p53 and p21 in endometrial or ovarian cancer cell lines were investigated and compared with that in normal cells by Western blots. (2) The effects of MEK-inhibitor and/or anti-estrogen, and siRNA of MDM2 on cell growth, tumorigenicity in nude mice were examined. Results.: The MDM2 level was enhanced in cancer cells compared with normal cells. Treatment with MEK inhibitor(U0126) resulted in a reduced MDM2 level, enhanced p53 and p21 levels and inhibited cell growth by the induction of premature senescence. The effect of MEK inhibitor on cell growth was affected by ER levels and functions. Treatment with low-dose MEK inhibitor in combination with anti-estrogen (ICI182,780) had a more inhibitory effect on cell growth compared to treatment with MEK inhibitor or anti-estrogen alone in cancer cells. Down-regulation of the MDM2 level by siRNA resulted in the inhibition of growth in cancer cells. Conclusion.: The blockage of the MAPK/ER/MDM2 pathway suppress cell proliferation and it is supposed as a new molecular target therapy in estrogen-dependent gynecologic cancers, such as endometrial or ovarian cancer.

本文言語英語
ページ(範囲)341-350
ページ数10
ジャーナルGynecologic Oncology
105
2
DOI
出版ステータス出版済み - 5 2007

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 産婦人科学

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