R-(+)-perillyl alcohol-induced cell cycle changes, altered actin cytoskeleton, and decreased ras and p34(cdc2) expression in colonic adenocarcinoma SW480 cells

Monoterpenes as S-(-)-perillyl alcohol (PA) have been shown to inhibit the isoprenylation of such growth regulatory proteins as ras. In this study, we investigated the effects of the R-(+) enantiomer of PA on cell cycle, sign aling, and cytoskeletal control in the colonic adenocarcinoma cell line SW4 80, which carries a K-ras mutation. Cell cycle analysis by flow cytometry o f SW480 cells treated with 1 mM PA for 24 hours demonstrated an increase in the number of cells in G0/G1 with a decrease in S phase, compared with unt reated control cells. These cell cycle changes correlated with an inhibitio n of protein isoprenylation from C-14-mevalonate and decreased expression o f the cell cycle regulatory kinase p34(cdc2). Additionally, PA-treated cell s acquired a flattened morphology with a condensation of cytoskeletal actin spikes to the periphery. This was in contrast to treatment with 15 mu M me vinolin (MVN), a direct mevalonate synthesis inhibitor, which imparted to S W480 cells a more rounded and spindly morphology, associated with the depol ymerization of actin microfilaments. Together, these data suggest that fluc tuations in mevalonate and isoprenoid pools may involve different morpholog ic phenomenon. Because ras mediated signaling is related to the organizatio n of the actin cytoskeleton, we investigated the effects of PA on the isopr enylation of ras. Although MVN treatment inhibited ras farnesylation, PA tr eatment decreased the expression of total ras protein. In summary, R-(+)-PA -induced cell signaling events correlated with alterations in the organizat ion of cytoskeletal actin and decreased protein expression of growth regula tory proteins, such as ras and cdc2 kinase. These effects may contribute to the growth inhibitory activity of R-(+)-PA. (J. Nutr. Biochem. 10:19-30, 1 999) (C) Elsevier Science Inc. 1999. All rights reserved.