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

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