| An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer. | |
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MedLine Citation:
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PMID: 17306348 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Shin Suga; Kiyoko Kato; Tatsuhiro Ohgami; Asako Yamayoshi; Sawako Adachi; Kazuo Asanoma; Shinichiro Yamaguchi; Takahiro Arima; Katsuyuki Kinoshita; Norio Wake |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-02-15 |
Journal Detail:
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Title: Gynecologic oncology Volume: 105 ISSN: 0090-8258 ISO Abbreviation: Gynecol. Oncol. Publication Date: 2007 May |
Date Detail:
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Created Date: 2007-04-23 Completed Date: 2007-05-31 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0365304 Medline TA: Gynecol Oncol Country: United States |
Other Details:
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Languages: eng Pagination: 341-50 Citation Subset: IM |
Affiliation:
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Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyushu University, Maidadhi 3-1-1, Higashi-ku, Fukuoka, Japan. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Growth Processes
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drug effects,
physiology Cell Line, Tumor Down-Regulation Endometrial Neoplasms / drug therapy, metabolism*, pathology, therapy* Enzyme Inhibitors / pharmacology Estradiol / analogs & derivatives, pharmacology Estrogen Receptor Modulators / pharmacology Estrogen Receptor alpha / antagonists & inhibitors*, metabolism Female Humans MAP Kinase Kinase Kinases / antagonists & inhibitors*, metabolism MAP Kinase Signaling System Ovarian Neoplasms / drug therapy, metabolism*, pathology, therapy* Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*, biosynthesis, genetics, metabolism Proto-Oncogene Proteins p21(ras) / metabolism RNA, Small Interfering / genetics Tumor Suppressor Protein p53 / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Estrogen Receptor Modulators; 0/Estrogen Receptor alpha; 0/RNA, Small Interfering; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 129453-61-8/fulvestrant; 50-28-2/Estradiol; EC 2.7.11.25/MAP Kinase Kinase Kinases; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras); EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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