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

N Arber1, E K Han, A Sgambato

  • 1Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA.

Gastroenterology
|December 12, 1997
PubMed
Abstract

Insights

Colorectal cancer cells with c-K-ras mutations show reduced sensitivity to the chemopreventive drug sulindac sulfide. This resistance may stem from decreased expression of the pro-apoptotic protein Bak.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Cancer Research

Background:

  • c-K-ras mutations are frequent in colon neoplasms.
  • Understanding their impact on cancer prevention is crucial.

Purpose of the Study:

  • To investigate how c-K-ras mutations affect cellular response to sulindac, a chemopreventive agent.
  • To elucidate the mechanisms underlying sulindac resistance in mutated cells.

Main Methods:

  • Utilized rat intestinal cell line IEC-18 and its c-K-ras-transformed derivatives.
  • Assessed cell cycle, apoptosis, and gene expression changes upon sulindac sulfide treatment.
  • Employed flow cytometry, DNA fragmentation assays, and immunoblotting.

Main Results:

  • Sulindac sulfide inhibited growth and induced apoptosis more effectively in parental cells than in ras-transformed cells.
  • Ras-transformed cells exhibited lower levels of pro-apoptotic Bak protein, which did not increase with sulindac sulfide treatment.
  • Sulindac sulfide reduced cyclin D1 protein and associated kinase activity in both cell types.

Conclusions:

  • c-K-ras-transformed enterocytes display relative resistance to sulindac sulfide.
  • This resistance is potentially linked to the specific downregulation of Bak expression.

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