Abstract 4115: Pituitary adenylate cyclase activating polypeptide causes the transactivation of epidermal growth factor receptors in lung cancer cells

Abstract

Abstract Pituitary adenylate cyclase activating polypeptide (PACAP) is an autocrine growth factor for some lung cancer cells. The activated PAC1 receptor (R) causes phosphatidylinositol turnover, elevates cyclic AMP and increases proliferation of lung cancer cells (Zia et al., Cancer Res. 55:4886 (1995)). PAC1R mRNA is present in NSCLC cell line NCI-H838, which has epidermal growth factor (EGF)R. PACAP or EGF stimulated the proliferation of NCI-H838 cells whereas PACAP(6-38) or gefitinib inhibited growth. To investigate the cellular basis of these actions, the ability of PACAP to alter EGFR function was investigated using NSCLC cells. PACAP, but not the closely related vasoactive intestinal peptide (VIP) significantly increased EGFR tyrosine phosphorylation (4-fold) 2 min after addition to NCI-H838 cells. The ability of PACAP to increase EGFR or ERK tyrosine phosphorylation was inhibited by PACAP(6-38) (PAC1R antagonist), gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), or antibody to transforming growth factor (TGF) α. These results suggest that PACAP may increase the rate of release of TGFα from NCI-H838 cells, resulting in elevated EGFR tyrosine phosphorylation. PACAP stimulation of EGFR tyrosine phosphorylation was inhibited by addition of N-acetylcysteine (anti-oxidant), tiron (superoxide scavenger), DPI (NADPH oxidase inhibitor) or U-73122 (Phospholipase C inhibitor) but not H89 (protein kinase A inhibitor) to NCI-H838 cells. These results indicate that PACAP, a growth factor for NSCLC, causes transactivation of the EGFR in an oxygen-dependent manner that involves phospholipase C but not protein kinase A. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4115.