Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells

Banke Agarwal, Balazs Halmos, Aleksander S. Feoktistov, Petr Protiva, William G. Ramey, Ming Chen, Charalabos Pothoulakis, J. Thomas Lamont, Peter R. Holt

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

We earlier showed that lovastatin potentiated the chemo-preventive effects of sulindac against colon neoplasia in a rodent model and augments apoptosis induced by 5-FU and cisplatin in human colon cancer cells. In the present study, we investigated effects of lovastatin in spontaneously immortalized rat intestinal epithelial cells, IEC-18 and their K-ras transformed clones. Lovastatin induced morphologic changes (cell rounding and detachment) and apoptosis that were not influenced by K-ras mutations, but were prevented by geranylgeranyl-pyrophosphate or by mevalonate. Clostridium difficile toxin B, which directly inactivates rho, induced similar morphologic changes and apoptosis. Cycloheximide prevented these effects of lovastatin, but not C. difficile toxin B. Lovastatin decreased the amounts of membrane bound rhoA and rhoB. Cycloheximide and geranylgeranylpyrophosphate prevented lovastatin induced morphologic changes and apoptosis but did not inhibit lovastatin-induced changes in membrane translocation of rho. Our data suggest that lovastatin induces morphologic changes and apoptosis by inhibiting geranylgeranylation of small GTPases of the rho family and thereby inactivating them. Restoration of membrane translocation of rho is not necessary for preventing lovastatin-induced morphologic changes or apoptosis.

Original languageEnglish (US)
Pages (from-to)521-528
Number of pages8
JournalCarcinogenesis
Volume23
Issue number3
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

Fingerprint Dive into the research topics of 'Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells'. Together they form a unique fingerprint.

  • Cite this

    Agarwal, B., Halmos, B., Feoktistov, A. S., Protiva, P., Ramey, W. G., Chen, M., Pothoulakis, C., Lamont, J. T., & Holt, P. R. (2002). Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis, 23(3), 521-528. https://doi.org/10.1093/carcin/23.3.521