Effect of lovastatin on the cytotoxicity of ricin, modeccin, Pseudomonas toxin, and diphtheria toxin in brefeldin A-sensitive and -resistant cell lines.
Lovastatin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibits the biosynthesis of cholesterol and the prenylation of proteins. In this study, we have found that lovastatin inhibited the cytotoxicities of modeccin, ricin, Pseudomonas toxin, and diphtheria toxin in Vero and a brefeldin A (BFA)-resistant mutant of Vero cells (BER-40) to different extents. Among these toxins tested, the cytotoxicity of modeccin was most strongly inhibited by lovastatin in a dose-dependent manner. The protective effect of lovastatin was completely reversed by the addition of mevalonic acid, while the addition of cholesterol had no effect on the cytotoxicity of modeccin in lovastatin-treated cells. These results suggest that prenylated proteins are involved in the intoxication process of modeccin. The addition of cycloheximide to the growth medium also reversed the protective effect of lovastatin, suggesting a requirement of de novo protein synthesis for the protection by lovastatin against toxins. In contrast to Vero and BER-40 cells, no significant effect of lovastatin was observed in naturally BFA-resistant cell lines, PtK1 and MDCK cells, even though similar morphological changes and disassembly of the actin microfilaments were induced by lovastatin in these cell lines as observed in Vero and BER-40 cells. Lovastatin did not affect the binding and internalization of ricin and modeccin in Vero and BER-40 cells. Our results suggest that prenylated cellular proteins are involved in intracellular trafficking or processing of protein toxins, especially modeccin. In PtK1 and MDCK cells, such intracellular vesicle trafficking of protein toxins may be regulated by lovastatin-resistant mechanisms.
Oda
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Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799.
Wu
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D036002:ADP Ribose Transferases; D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000818:Animals; D001427:Bacterial Toxins; D020126:Brefeldin A; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D004167:Diphtheria Toxin / Q000633:toxicity*; D004285:Dogs; D005098:Exotoxins / Q000633:toxicity*; D066298:In Vitro Techniques; D037102:Lectins / Q000633:toxicity*; D008148:Lovastatin / Q000494:pharmacology*; D037121:Plant Lectins; D054790:Ribosome Inactivating Proteins, Type 2; D012276:Ricin / Q000633:toxicity*; D014709:Vero Cells; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D020126:Brefeldin A; D003517:Cyclopentanes; D004167:Diphtheria Toxin; D005098:Exotoxins; D037102:Lectins; D008148:Lovastatin; D037121:Plant Lectins; D054790:Ribosome Inactivating Proteins, Type 2; D012276:Ricin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C016004:modeccin