Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells.
We earlier showed that lovastatin potentiated the chemopreventive 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 geranylgeranyl-pyrophosphate 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.
Agarwal
Banke
B
Department of Medicine and Department of Surgery, St Luke's-Roosevelt Hospital Center, College of Physicians and Surgeons, Columbia University, New York, NY 10025, USA.
Halmos
Balazs
B
Feoktistov
Aleksander S
AS
Protiva
Petr
P
Ramey
William G
WG
Chen
Ming
M
Pothoulakis
Charalabos
C
Lamont
J Thomas
JT
Holt
Peter R
PR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D007422:Intestines / Q000166:cytology / Q000187:drug effects*; D008148:Lovastatin / Q000494:pharmacology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D011106:Polyisoprenyl Phosphates; C031815:toxB protein, Clostridium difficile; D003513:Cycloheximide; D008148:Lovastatin; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate