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J. Biol. Chem., Vol. 266, Issue 26, 17679-17685, 09, 1991
PL Crowell, RR Chang, ZB Ren, CE Elson and MN Gould
Limonene has chemotherapeutic activity against chemically induced rat
mammary carcinomas, many of which contain activated ras genes. Given the
recent discovery of the post-translational modification of p21ras and other
cell growth-associated proteins by intermediates in the mevalonic acid
pathway, and the common biochemical origins of limonene and these isoprene
products, we investigated the effect of limonene on protein isoprenylation.
NIH3T3 and human mammary epithelial cells were incubated with lovastatin
and [2-14C]mevalonolactone in the absence and presence of limonene. Labeled
proteins were then subjected to sodium dodecyl sulfate-polyacrylamide gel
electrophoresis and fluorography. Limonene inhibited isoprenylation of a
class of cellular proteins of 21- 26 kDa, including p21ras and possibly
other small GTP-binding proteins, in a dose-dependent manner in both cell
lines. In contrast, limonene did not affect the isoprenylation of several
other proteins, including nuclear lamins. Limonene is metabolized
extensively in vivo but not in cultured cells. The two major rat serum
metabolites of limonene, perillic acid and dihydroperillic acid, were more
potent than limonene in the inhibition of isoprenylation. These results
demonstrate that limonene selectively inhibits isoprenylation of 21-26-kDa
proteins at a point in the mevalonic acid pathway distal to 3-hydroxy-3-
methylglutaryl coenzyme A reductase, and they provide a plausible
explanation for its chemotherapeutic activity. Inhibition of isoprenylation
of proteins such as p21ras and other small GTP-binding proteins would alter
their intracellular localization and, hence, disrupt their biological
activity.
Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites
Department of Human Oncology, University of Wisconsin-Madison 53792.
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