title: A novel Ras antagonist regulates both oncogenic Ras and the tumor suppressor p53 in colon cancer cells.
abstract: BACKGROUND
  In colon cancer, K-Ras oncogenes, which appear to be linked to chemoresistance and poor prognosis, are activated in more than 50% of cases, whereas the tumor suppressor gene p53 is mutationally altered in about 70% of all cases. The transcription factor p53, which is frequently mutated at codon 273, maintains wild-type configuration and possibly carries out residual functions. Although blocking of activated K-Ras may constitute a rational therapeutic concept for this treatment-resistant malignancy, a strategy influencing both oncogenic Ras and the tumor suppressor p53 may be even more promising.
  
  
  METHODS
  We evaluated the effects of S-trans, trans-farnesyl-thiosalicylic acid (FTS), a novel Ras antagonist on human SW480 and HT-29 colon cancer cells, which both harbor a p53 His273 mutation but express activated K-Ras and wild-type, but overexpressed, H-Ras, respectively. Besides cell growth and morphology, levels of cellular Ras proteins, regulation of p53 and p21(waf1/cip1) expression were analyzed by immunoblotting. The cell cycle arresting potential of FTS was quantified by flow cytometry.
  
  
  RESULTS
  We demonstrate that FTS treatment alters the morphology and blocks the growth of SW480 and HT-29 colon cancer cells by both reducing the total amount of Ras and up-regulating the tumor suppressor p53. Furthermore, FTS caused an upregulation of the cyclin-cyclin-dependent kinase (CDK) inhibitor p21(waf1/cip1) and blocked the cell cycle. p53 antisense oligonucleotides not only reduced the level of p53 proteins but correspondingly also blocked the expression of p21(waf1/cip1) in FTS-treated colon cancer cells.
  
  
  CONCLUSIONS
  FTS, a unique compound capable of regulating both oncogenic Ras and the tumor suppressor p53 may prove particularly useful for the therapy of colon cancer and other treatment-resistant malignancies where Ras is altered and p53 is either wild-type or mutated in positions that allow residual p53 functions.
authors.affiliation: Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Halaschek-Wiener
authors.forename: V
authors.initials: V
authors.lastname: Wacheck
authors.forename: H
authors.initials: H
authors.lastname: Schlagbauer-Wadl
authors.forename: K
authors.initials: K
authors.lastname: Wolff
authors.forename: Y
authors.initials: Y
authors.lastname: Kloog
authors.forename: B
authors.initials: B
authors.lastname: Jansen
mesh_terms: D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016376:Oligonucleotides, Antisense; D012459:Salicylates; D016159:Tumor Suppressor Protein p53; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018844:Cyclin-Dependent Kinases; D015689:Oncogene Protein p21(ras)