Prenylated proteins and lymphocyte proliferation: Inhibition by d‐limonene and related monoterpenes

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Abstract
The aim of the present study was to explore the role of post‐translational isoprenoid modification of cellular proteins in the proliferation of human lymphocytes. We here report that treatment of phytohemagglutinin‐stimulated peripheral blood mononuclear cells with monoterpenes including d‐limonene, perillic acid and perillyl alcohol (0.5–5 mM) which selectively inhibit the isoprenylation of 21–26‐kDa proteins resulted in a dose‐dependent inhibition of DNA synthesis. Cell cycle analysis revealed that perillic acid arrested cells in G1 and prevented cells from entering S phase in a manner similar to that induced by the specific 3‐hydroxy‐3‐methylglutaryl‐CoA reductase inhibitor, compactin. However, unlike compactin, the perillic acid‐induced effects on lymphocyte proliferation were not prevented by addition of mevalonate. We also examined the incorporation of [3H]mevalonate into proteins in resting and phytohemagglutinin‐stimulated lymphocytes during the first 30 h of culture. While in unstimulated lymphocytes radioactivity was predominantly incorporated into a cluster of 21–26‐kDa proteins, mitogenic stimulation was associated with a striking increase in [3H]mevalonate incorporation into a protein (≈︁68 kDa) with migration characteristics similar to that of nuclear lamin B. Treatment of phytohemagglutinin‐stimulated lymphocytes with 5 mM d‐limonene, 2.5 mM perillic acid or 1.25 mM perillyl alcohol strongly suppressed [3H]mevalonate‐labeling of proteins to a degree that correlated with the level of DNA synthesis inhibition. These findings suggest that those mevalonate‐derived products required for lymphocyte proliferation may include one or more isoprenylated proteins and that the isoprenylation of these proteins is required for cell cycle progression.