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We have previously shown that intraperitoneal injections of the Ras inhibitor <jats:italic>S<\/jats:italic>\u2010<jats:italic>trans<\/jats:italic>, <jats:italic>trans<\/jats:italic>\u2010farnesylthiosalicyclic acid (FTS) blocks Ras activation and prevents heptocarcinoma development in rats receiving weekly injections of the carcinogene diethylnitrosamine (DEN) for 16\u2009wk. Using this in vivo model, we evaluated the relationship between the tumor preventive effect of Ras inhibition and activation of downstream signaling pathways, cell proliferation, cell cycle events, and angiogenesis. Western blotting, quantitative PCR, immunohistochemistry, and transcription factor activity assays were used. DEN\u2010induced activation of NFkB and Stat3 was abrogated by FTS treatment. FTS treatment showed no effect on DEN\u2010induced elevation of TNF\u03b1, interleukin 6 and TLR4, known activators of these transcription factors. FTS significantly reduced phosphorylation of the MAPkinase p38 and of the p70S6 kinase, a surrogate marker for mTor activation, without affecting ERK and AKT phosphorylation. These events were associated with reduced c\u2010myc and cyclin D expression as well as reduced cell proliferation in transformed, GSTp\u2010positive hepatocytes. Moreover, FTS treatment shifted cell proliferation from transformed hepatocytes to apparently normal, GSTp negative hepatocytes. FTS treatment did not down\u2010regulate expression of angiogenesis markers HIF\u03b1, VEGF, VEGF receptor1, and placenta growth factor. FTS treatment inhibits important signaling pathways involved in cellular proliferation leading to strongly reduced proliferation of transformed hepatocytes without affecting normal hepatocytes. This re\u2010adjustment of the proliferation balance likely contributes to the tumor preventive of FTS in the context of Ras inhibition in hepatocarcinogenesis. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/mc.20849","type":"journal-article","created":{"date-parts":[[2011,9,1]],"date-time":"2011-09-01T07:10:03Z","timestamp":1314861003000},"page":"816-825","source":"Crossref","is-referenced-by-count":10,"title":["Ras inhibition in hepatocarcinoma by <i>S<\/i>\u2010<i>trans<\/i>\u2010<i>trans<\/i>\u2010farnesylthiosalicyclic acid: Association of its tumor preventive effect with cell proliferation, cell cycle events, and 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