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 language | English (US) |
|---|---|
| Pages (from-to) | 521-528 |
| Number of pages | 8 |
| Journal | Carcinogenesis |
| Volume | 23 |
| Issue number | 3 |
| State | Published - 2002 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
Cite this
Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. / Agarwal, Banke; Halmos, Balazs; Feoktistov, Aleksander S.; Protiva, Petr; Ramey, William G.; Chen, Ming; Pothoulakis, Charalabos; Lamont, J. Thomas; Holt, Peter R.
In: Carcinogenesis, Vol. 23, No. 3, 2002, p. 521-528.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells
AU - Agarwal, Banke
AU - Halmos, Balazs
AU - Feoktistov, Aleksander S.
AU - Protiva, Petr
AU - Ramey, William G.
AU - Chen, Ming
AU - Pothoulakis, Charalabos
AU - Lamont, J. Thomas
AU - Holt, Peter R.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036207642&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036207642&partnerID=8YFLogxK
M3 - Article
VL - 23
SP - 521
EP - 528
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 3
ER -