A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes

N. Arber, E. K.H. Han, A. Sgambato, G. A. Piazza, T. M. Delohery, M. Begemann, C. M. Weghorst, N. H. Kim, R. Pamukcu, D. J. Ahnen, J. C. Reed, I. B. Weinstein, P. R. Holt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Background and Aims: Mutations of c-K-ras occur commonly in colonic neoplasms. The aim of this study was to determine how c-K-ras mutations alter the responses to the chemopreventive agent sulindac. Methods: The parental rat intestinal cell line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac sulfide. Cell cycle distribution was determined by flow-cytometric analysis (fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering), flow cytometry, and microscopy, and changes in gene expression by immunoblotting. Results: Sulindac sulfide inhibited cell growth and induced apoptosis in a time- and dose-dependent manner more rapidly in and at lower concentrations in parental cells than ras-transformed cells. Expression of the sulindac sulfide arrested cells in G0/G1, but cells entered apoptosis throughout the cell cycle. Proapoptotic protein Bak was relatively high n untreated parental cells and increased markedly after sulindac sulfide but was low in untreated ras-transformed cells and did not increase after sulindac sulfide. Expression of other Bcl-2 family members was unchanged after sulindac sulfide. However, sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1-associated kinase activity. Conclusions: c-K-ras-transformed enterocytes are relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis, which may result from specific reduction of bak expression.

Original languageEnglish
Pages (from-to)1892-1900
Number of pages9
Issue number6
StatePublished - 1997
Externally publishedYes


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