An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer.
An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer.
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DOI：
10.1016/j.ygyno.2006.12.030
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发表时间：
2007-05
影响因子：
4.7
通讯作者：
S. Suga;Kiyoko Kato;T. Ohgami;A. Yamayoshi;Sawako Adachi;K. Asanoma;S. Yamaguchi;T. Arima;K. Kinoshita;N. Wake
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文献类型：
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作者：
S. Suga;Kiyoko Kato;T. Ohgami;A. Yamayoshi;Sawako Adachi;K. Asanoma;S. Yamaguchi;T. Arima;K. Kinoshita;N. Wake
目的：我们先前证明Ras/ER/MDM 2通路对于NIH 3 T3细胞转化是关键的。在这项研究中，我们研究了阻断这一途径对妇科癌细胞生长的影响。方法：(1)采用Western blot方法检测子宫内膜癌和卵巢癌细胞系中MDM 2、ER、p53和p21的表达水平，并与正常细胞进行比较。(2)检测MEK抑制剂和/或抗雌激素以及MDM 2的siRNA对细胞生长和裸鼠成瘤性的影响。结果：与正常细胞相比，癌细胞中的MDM 2水平增强。用MEK抑制剂（U 0126）处理导致MDM 2水平降低，p53和p21水平升高，并通过诱导过早衰老来抑制细胞生长。MEK抑制剂对细胞生长的影响受ER水平和功能的影响。在癌细胞中，与单独使用MEK抑制剂或抗雌激素治疗相比，使用低剂量MEK抑制剂与抗雌激素（ICI 182，780）联合治疗对细胞生长具有更强的抑制作用。通过siRNA下调MDM 2水平导致癌细胞生长的抑制。结论：阻断MAPK/ER/MDM 2通路可抑制细胞增殖，有望成为雌激素依赖性妇科肿瘤（如子宫内膜癌、卵巢癌）的新的分子靶向治疗手段。
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.