Lovastatin induces apoptosis by inhibiting mitotic and post-mitotic events in cultured mesangial cells.
Lovastatin, an inhibitor of protein prenylation, was reported to inhibit DNA synthesis and induce apoptosis in cultured cells. This report describes the morphological consequences of lovastatin treatment. Lovastatin (50 microM) induced mesangial cell rounding and disassembly of actin stress fibers within 24 to 48 h. After 48 to 72 h of lovastatin treatment, the cells detached from the substratum and underwent apoptotic cell death as evidenced by condensed nuclear chromatin, nuclear fragmentation, cell blebbing and decrease in cell size. Time lapse cinematography revealed that lovastatin caused cell rounding by either inhibiting cytokinesis or cell spreading following cytokinesis. Lovastatin-induced cell rounding, detachment, and apoptosis were dependent upon cell proliferation. These effects were prevented by serum deprivation to inhibit cell proliferation or by plating cells at densities which resulted in contact inhibition of cell growth. Lovastatin-induced mesangial cell rounding and apoptosis were also prevented by the inclusion of the isoprenoids all-trans-farnesol or all-trans-geranylgeraniol in the incubation medium. These results indicate that the effects of lovastatin were mediated by inhibition of protein isoprenylation because exogenous all-trans-geranylgeraniol can be used only in protein prenylation. The small GTP-binding protein RhoA, which may be important for cell spreading and cytokinesis, accumulated in the cytosol following treatment with lovastatin, suggestive of its inactivation. This effect was also prevented by the inclusion of either farnesol or geranylgeraniol in the incubation medium. Thus, lovastatin-induced apoptosis in mesangial cells occurs by interfering with prenylation dependent mitotic and post-mitotic events.
Ghosh
P M
PM
Department of Pathology, University of Texas Health Science Center, San Antonio 78284-7750, USA.
Mott
G E
GE
Ghosh-Choudhury
N
N
Radnik
R A
RA
Stapleton
M L
ML
Ghidoni
J J
JJ
Kreisberg
J I
JI
D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D008148:Lovastatin / Q000494:pharmacology*; D008854:Microscopy, Electron; D018715:Microscopy, Video; D008938:Mitosis / Q000187:drug effects*; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D020742:rhoA GTP-Binding Protein
D000199:Actins; D004224:Diterpenes; D005204:Farnesol; D008148:Lovastatin; C017338:geranylgeraniol; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D001973:Bromodeoxyuridine