{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:10:10Z","timestamp":1791382210616,"version":"4.3.3"},"reference-count":29,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2012,8,10]],"date-time":"2012-08-10T00:00:00Z","timestamp":1344556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives\/Hypothesis:<\/jats:title><jats:p>The purpose of this study was to evaluate the Ras GTPase (Ras) to extracellular signal\u2010regulated kinase (ERK) pathway in vestibular schwannoma (VS) cell cultures and patient excised schwannoma tumors. Mitogen\u2010activated protein kinase kinase (MEK) inhibitor CI\u20101040 (PD184352) was utilized to evaluate the effect of specific MEK inhibition on benign schwannoma cell culture proliferation and apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design:<\/jats:title><jats:p>Prospective evaluation of human schwannoma cell lines and tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Western blotting was completed with phospho\u2010antibodies for proteins in the Ras\u2010ERK pathway. Increasing concentrations of CI\u20101040 were utilized in schwannoma cell cultures to evaluate cell proliferation and apoptosis. Proliferation was measured with the 3\u2010[4,5\u2010dimethylthiazol\u20102\u2010yl]\u20102,5\u2010diphenyl tetrazolium bromide proliferation assay, and apoptosis was monitored with flow cytometry of annexin V\/propidium iodide\u2010stained cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>The most consistent Ras\u2010ERK pathway alterations were found in phospho\u2010MEK and ERK. Phospho\u2010MEK was not overexpressed in the schwannoma cell lines, but six out of 10 VS showed significant increases compared to benign Schwann cell controls. Similarly, nine of 10 VS tumors showed increased phospho\u2010ERK expression. CI\u20101040 showed significantly reduced schwannoma cell proliferation at the 50 and 100 \u03bcM (IC<jats:sub>50<\/jats:sub> 20 \u03bcM and 30 \u03bcM) concentrations when compared to carrier only controls in two out three schwannoma cell lines. The remaining schwannoma cell line was relatively refractory to the antiproliferative effects of CI\u20101040 at doses up to 100 \u03bcM (IC<jats:sub>50<\/jats:sub> 58 \u03bcM). Cumulative data of four separate schwannoma cell lines demonstrated that apoptosis was increased in treated schwannoma cells at CI\u20101040 concentrations of 50 and 100 \u03bcM at 72 hours.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>There is overexpression of phosphorylated (activated) proteins in the Ras\u2010ERK pathway in schwannoma cultures and tumors as compared to benign human Schwann cell culture controls. MEK inhibitor, CI\u20101040, created significantly decreased schwannoma cell proliferation and increased apoptosis in cell culture. These data justify the use of MEK inhibitors in animal treatment studies of VS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/lary.23472","type":"journal-article","created":{"date-parts":[[2012,8,10]],"date-time":"2012-08-10T18:03:42Z","timestamp":1344621822000},"page":"2269-2278","source":"Crossref","is-referenced-by-count":14,"title":["Inhibition of MEK pathway in vestibular schwannoma cell culture"],"prefix":"10.1002","volume":"122","author":[{"given":"Brian A.","family":"Neff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen G.","family":"Voss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin L. 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