The cannabinoid receptors CB1 and CB2 are present on non-small cell lung cancer (NSCLC) biopsy specimens (Preet et al., 2011, Cancer Prev. Res. 4:65). CP55,940 and Win55,212-2 are mixed agonists which stimulate CB1 and CB2 cannabinoid receptors. G-protein coupled receptors (GPCR) for pituitary adenylate cyclase activating polypeptide (PACAP) regulate epidermal growth factor receptor (EGFR) tyrosine phosphorylation in NSCLC cells. Here the ability of cannabinoids to alter EGFR transactivation was investigated. PACAP stimulated EGFR tyrosine phosphorylation (PY1068) 4-fold using NCI-H838 and H1299 cells. CP55,940 and Win55,212-2 inhibited the ability of PACAP to increase EGFR tyrosine phosphorylation in lung cancer cells. By Western blot, cell lines NCI-H838 and NCI-H1299 had both CB1 and CB2 receptors. PACAP increased cAMP levels in NCI-H838 cells and CP55,940 inhibited the increase in cAMP caused by PACAP. In contrast, PACAP increased cytosolic Ca2+ in lung cancer cells, but CP55,940 did not alter the ability of PACAP to increase calcium in lung cancer cells. These results suggest that CP55,940 may inhibit adenylyl cyclase activity but not phosphatidylinositol turnover caused by addition of PACAP to lung cancer cells. Previously we found that PACAP increased tyrosine phosphorylation of focal adhesion kinase, paxillin and ERK in lung cancer cells (Moody et al., 2002, Reg. Peptides 109:135). CP55,940 inhibited the increase in tyrosine phosphorylation of focal adhesion kinase, paxillin and ERK caused by PACAP addition to lung cancer cells. Also, CP55.940 and Win55,212-2 inhibited the growth of NCI-H1299 and NCI-H838 cells. CP55,940 potentiated the growth inhibitory effects of gefitinib, an EGFR tyrosine kinase inhibitor. These results indicate that cannabinoids inhibit EGFR transactivation in lung cancer cells and potentiate gefitinib cytotoxicity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1091. doi:1538-7445.AM2012-1091