Effects of the antitumor agent perillyl alcohol on H-Ras vs. K-Ras farnesylation and signal transduction in pancreatic cells.

Background: Perillyl alcohol has chemotherapeutic activity against pancreas cancers that have a K-ras oncogene, and it inhibits the prenylation of Ras and other proteins in many cell types.

Materials And Methods: We tested the hypothesis that perillyl alcohol would impair Ras farnesylation and Ras signal transduction pathways in pancreatic tumor cells.

Results: In B12/13 pancreatic tumor cells that had a K-ras oncogene, perillyl alcohol inhibited total protein prenylation and decreased Ras farnesylation. However, the decrease in Ras farnesylation was not sufficient to affect Ras GTP/GDP ratios or MAP kinase phosphorylation. We then investigated the effects of perillyl alcohol on H-Ras vs. K-Ras. Interestingly, H-Ras, but not K-Ras, farnesylation was inhibited by perillyl alcohol, and perillyl alcohol inhibited MAP kinase phosphorylation in H-ras but not K-ras oncogene-transformed pancreatic cells.

Conclusions: The antitumor activity of perillyl alcohol against pancreatic cancers may stem from its ability to inhibit the prenylation of growth-regulatory proteins other than K-Ras, including H-Ras.