Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells
Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells
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DOI：
10.1093/carcin/23.3.521
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发表时间：
2002-03-01
期刊：
影响因子：
4.7
通讯作者：
Holt, PR
中科院分区：
文献类型：
--
作者：
Agarwal, B;Halmos, B;Holt, PR
我们先前在啮齿动物模型中发现，洛伐他汀增强了舒林酸对结肠肿瘤的化学预防作用，并增强了5-FU和顺铂诱导的人结肠癌细胞凋亡。在本研究中，我们研究了洛伐他汀在自发永生化的大鼠肠上皮细胞，IEC-18及其K-ras转化克隆中的作用。洛伐他汀诱导的形态学变化（细胞变圆和脱离）和细胞凋亡，不受K-ras突变的影响，但被阻止的香叶基香叶基焦磷酸或甲羟戊酸。直接灭活rho的艰难梭菌毒素B诱导了类似的形态学变化和凋亡。环己酰亚胺可阻断洛伐他汀的上述作用，但C.艰难梭菌毒素B。洛伐他汀降低膜结合rhoA和rhoB的量。放线菌酮和香叶基香叶基焦磷酸盐阻止洛伐他汀诱导的形态学变化和细胞凋亡，但不抑制洛伐他汀诱导的rho膜转位的变化。我们的数据表明，洛伐他汀诱导的形态变化和细胞凋亡，通过抑制牛儿基牛儿基化的小GTP酶的rho家族，从而使其失活。修复rho的膜转位对于防止洛伐他汀诱导的形态学改变或细胞凋亡不是必需的。
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.