Inhibition of farnesyl protein transferase and P21ras memebrane association by d-limonene in human pancreas tumor cells in vitro.

Abstract The monoterpene d-limonene inhibit the plasma-membrane associated P21ras expression and the post-translational isoprenylation of P21ras, a mechanism that may contribute to its efficacy in the chemoprevention and therapy of chemically induced rodent cancers and some human solid tumor cells. In the present study, the relative abilities of d-limonene to inhibit membrane associated P21ras expression in pancreas tumor cell (PaCa) was carried out with Western blotting, and the inhibition of farnesyl protein transferase (FTPase) activity during the Ras protein isoprenylation and cell proliferation were determined. Concomitantly, the effects of d-limonene on P21ras localization by immunohistochemistry and H-ras oncogene expression in PaCa tumor cell line by Northern blotting were observed. The results showed that d-limonene inhibited FPTase activity, thus to reduce P21H-ras isoprenylation. d-limonene could decrease P21ras membrane association and increase cytosolic accumulation of P21ras. This phenomenon was also noted when d-limonene-treated PaCa cells were stained immunohistochemically with anti-P21ras antibody. It is suggested that the inhibition of FPTase activity was closely related with the inhibiton of P21ras membrane association and the alteration of P21ras localization. Inhibition of farnesylation of P21ras altered their intracellular localization and, hence, disrupted their biological activity, but no relationship with H-ras oncogene expression was found.