Abstract 4534: Lung cancer epidermal growth factor receptors are transactivated by neurotensin

Abstract

Abstract Neurotensin (NT) is an autocrine growth factor for some lung cancer cells (Moody et al., Life Sci 36:1727(1985)). The NTS1 receptor (R), which causes phosphatidylinositol turnover, elevates cytosolic Ca2+ and increases proliferation of lung cancer cells, is blocked by SR48692 (Moody et al., Peptides 22:109 (2001)). Previously we found that NT caused tyrosine phosphorylation of focal adhesion kinase in non-small cell lung cancer (NSCLC) cells (Leyton et al., Eur. J. Pharm. 442:179 (2002)). Here the ability of NT to cause tyrosine phosphorylation of the epidermal growth factor (EGF)R in lung cancer cells was investigated. NT and NT8-13 but not NT1-8 caused tyrosine phosphorylation of the EGFR using NCI-H1299 or H345 cells. The transactivation of the EGFR caused by NT addition to lung cancer cells was inhibited by SR48692 (NTS1R antagonist) or gefitinib (EGFR tyrosine kinase inhibitor). NT significantly increased EGFR tyrosine phosphorylation (4-fold) after 0.5 min in a dose-dependent manner. The ability of NT to increase EGFR or ERK tyrosine phosphorylation was inhibited by PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), or antibody to transforming growth factor (TGF) α. By ELISA, NT stimulated significantly the release of TGFα from NCI-H838 cells. NT stimulation of EGFR tyrosine phosphorylation was inhibited by addition of N-acetylcysteine (anti-oxidant), tiron (superoxide scavenger), DPI (NADPH oxidase inhibitor). These results indicate that NT causes transactivation of lung cancer EGFR in an oxygen-dependent, Src-dependent manner resulting in activation of matrix metalloprotease and release of TGFα. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2011-4534