title: Ras inhibition in hepatocarcinoma by S-trans-trans-farnesylthiosalicyclic acid: association of its tumor preventive effect with cell proliferation, cell cycle events, and angiogenesis.
abstract: Activation of Ras and its downstream signaling pathways, likely contribute to the development of hepatocarcinoma. We have previously shown that intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) blocks Ras activation and prevents heptocarcinoma development in rats receiving weekly injections of the carcinogene diethylnitrosamine (DEN) for 16 wk. 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-induced activation of NFkB and Stat3 was abrogated by FTS treatment. FTS treatment showed no effect on DEN-induced elevation of TNFα, 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-myc and cyclin D expression as well as reduced cell proliferation in transformed, GSTp-positive hepatocytes. Moreover, FTS treatment shifted cell proliferation from transformed hepatocytes to apparently normal, GSTp negative hepatocytes. FTS treatment did not down-regulate expression of angiogenesis markers HIFα, 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-adjustment of the proliferation balance likely contributes to the tumor preventive of FTS in the context of Ras inhibition in hepatocarcinogenesis.
authors: Laboratory of Gastroenterology, St. Luc University Hospital, Université catholique de Louvain, Brussels, Belgium.
authors: Peter
authors: P
authors: Stärkel
authors: Nicolas
authors: N
authors: Charette
authors: Ivan
authors: I
authors: Borbath
authors: Tanja
authors: T
authors: Schneider-Merck
authors: Christine
authors: C
authors: De Saeger
authors: Jorge
authors: J
authors: Abarca
authors: Isabelle
authors: I
authors: Leclercq
authors: Yves
authors: Y
authors: Horsmans
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D015536:Down-Regulation; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D012459:Salicylates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D056741:Cyclin D; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D012459:Salicylates; C494088:Stat3 protein, rat; C093323:farnesylthiosalicylic acid; D004052:Diethylnitrosamine; D005204:Farnesol; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins