TY - JOUR
T1 - Lovastatin and simvastatin are modulators of the proteasome
AU - Wójcik, Cezary
AU - Bury, Marcin
AU - Stoklosa, Tomasz
AU - Giermasz, Adam
AU - Feleszko, Wojciech
AU - Mlynarczuk, Izabella
AU - Pleban, Eliza
AU - Basak, Grzegorz
AU - Omura, Satoshi
AU - Jakóbisiak, Marek
N1 - Funding Information:
We thank Dr Sherwin Wilk (Mount Sinai School of Medicine, New York, NY, USA) for his generous gift of the purified pituitary proteasome and proteasome substrates as well as for his helpful discussions during the preparation of the manuscript. The work was supported by the KBN grant 4 P05A 084 16 and the ISDS minigrant 1M15/S/99 from the Warsaw Medical Academy to C.W.
PY - 2000
Y1 - 2000
N2 - Lovastatin and simvastatin are HMG-CoA reductase inhibitors widely used as antihyperlipidemic drugs, which also display antiproliferative properties. In the present paper, we provide evidence that both lovastatin and simvastatin are modulators of the purified bovine pituitary 20 S proteasome, since they mildly stimulate the chymotrypsin-like activity and inhibit the peptidylglutamylpeptide hydrolyzing activity without interfering with the trypsin-like activity. However, those effects are only observed when the closed ring forms of the drugs are used, while the opened ring form of lovastatin acts as a mild inhibitor of the chymotrypsin like activity. The closed ring form of lovastatin is much more potent as a cytotoxic agent on the Colon-26 (C-26) colon carcinoma cell line than the opened ring form, which is only mildly cytostatic. Moreover, neither the cytotoxic effects nor the effects on 20 S proteasome activities are prevented by mevalonate, which by itself inhibits the trypsin-like activity of the proteasome. Neither the opened ring nor the closed ring form of lovastatin induces an accumulation of ubiquitin-protein conjugates, which is observed after treatment with lactacystin, a selective proteasome inhibitor. In contrast with the opened ring form of lovastatin, the closed ring form induces the disappearance of detectable p27(kip1) from C-26 cells. Altogether, our results indicate that the closed ring form of lovastatin induces cytotoxic effects independent of its HMG-CoA inhibiting activity, however, those effects are mediated by a complex modulation of proteasome activity rather than by inhibition of the 20 S proteasome. (C) 2000 Elsevier Science Ltd.
AB - Lovastatin and simvastatin are HMG-CoA reductase inhibitors widely used as antihyperlipidemic drugs, which also display antiproliferative properties. In the present paper, we provide evidence that both lovastatin and simvastatin are modulators of the purified bovine pituitary 20 S proteasome, since they mildly stimulate the chymotrypsin-like activity and inhibit the peptidylglutamylpeptide hydrolyzing activity without interfering with the trypsin-like activity. However, those effects are only observed when the closed ring forms of the drugs are used, while the opened ring form of lovastatin acts as a mild inhibitor of the chymotrypsin like activity. The closed ring form of lovastatin is much more potent as a cytotoxic agent on the Colon-26 (C-26) colon carcinoma cell line than the opened ring form, which is only mildly cytostatic. Moreover, neither the cytotoxic effects nor the effects on 20 S proteasome activities are prevented by mevalonate, which by itself inhibits the trypsin-like activity of the proteasome. Neither the opened ring nor the closed ring form of lovastatin induces an accumulation of ubiquitin-protein conjugates, which is observed after treatment with lactacystin, a selective proteasome inhibitor. In contrast with the opened ring form of lovastatin, the closed ring form induces the disappearance of detectable p27(kip1) from C-26 cells. Altogether, our results indicate that the closed ring form of lovastatin induces cytotoxic effects independent of its HMG-CoA inhibiting activity, however, those effects are mediated by a complex modulation of proteasome activity rather than by inhibition of the 20 S proteasome. (C) 2000 Elsevier Science Ltd.
KW - Lactacystin
KW - Lovastatin
KW - Proteasome
KW - Simvastatin
KW - Ubiquitin
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U2 - 10.1016/S1357-2725(00)00044-3
DO - 10.1016/S1357-2725(00)00044-3
M3 - Article
C2 - 11084375
AN - SCOPUS:0033739334
SN - 1357-2725
VL - 32
SP - 957
EP - 965
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
IS - 9
ER -