Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth

We investigated the effect of 2-methyl-arachidonyl-2'-fluoro-ethylamide (Me t-F-AEA), a stable analog of the endocannabinoid anandamide, on a rat thyro id epithelial cell line (FRTL-5) transformed by the K-ras oncogene, and on epithelial tumors derived from these cells. Met-F-AEA effect in vivo was ev aluated in a nude mouse xenograft model, where K-ras-transformed (KiMol) ce lls were implanted subcutaneously. Met-F-AEA (0.5 mg/kg/dose) induced a dra stic reduction in tumor volume. This effect was inhibited by the CB1 recept or antagonist SR141716A (0.7 mg/kg/dose) and was accompanied by a strong re duction of K-ras activity. Accordingly, KiMol cells and tumors express CB1 receptors. Met-F-AEA inhibited (IC50 similar to5 muM) the proliferation in vitro and the transition to the S phase of KiMol cells and it reduced K-ras activity; these effects were antagonized by SR141716A. Met-F-AEA cytostati c action was significantly smaller in nontransformed FRTL-5 cells than in K iMol cells. Met-F-AEA treatment exerted opposite effects on the expression of CB1 receptors in KiMol and FRTL-5 cells, with a strong up-regulation in the former case and a suppression in nontransformed cells. The data suggest that: 1) Met-F-AEA inhibits ras oncogene-dependent tumor growth in vivo th rough CB1 cannabinoid receptors; and 2) responsiveness of FRTL-5 cells to e ndocannabinoids depends on whether or not they are transformed by K-ras.