A novel Ras antagonist regulates both oncogenic Ras and the tumor suppressor p53 in colon cancer cells.

J. Halaschek-Wiener*, V. Wacheck, H. Schlagbauer-Wadl, K. Wolff, Y. Kloog, B. Jansen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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. MATERIALS AND 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.

Original languageEnglish
Pages (from-to)693-704
Number of pages12
JournalMolecular Medicine
Volume6
Issue number8
DOIs
StatePublished - Aug 2000
Externally publishedYes

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