Abstract 2125: G-protein coupled receptors for cholecystokinin regulate transactivation of EGF receptors in lung cancer cells

Abstract

Abstract Cholecystokinin (CCK) receptors (CCK-AR and CCK-BR) are G-protein coupled receptors (GPCR) which are present on lung cancer cells (Yoder and Moody, Peptides 1987; 8: 103). CCK stimulates the proliferation of NCI-H345 cells, whereas the CCK-B receptor antagonist CI-988 inhibits proliferation (Moody et al., JPET 2001; 299: 1154). Peptide receptors for some gastrointestinal hormones/neurotransmitters mediate lung cancer growth by causing EGFR transactivation, but it is unknown if this occurs with CCK-BR. CCK-BR mRNA was detected in NCI-H345 and H727 lung cancer cells. Addition of CCK-8 or gastrin I (100 nM) to NCI-H345 or H727 cells, which have wild type EGFR, increased EGFR Tyr1068 phosphorylation after 5 min. The ability of CCK-8 to cause EGFR or ERK tyrosine phosphorylation was blocked by CI-988 (CCK-BR antagonist), gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), tiron (superoxide scavenger) and U-73122 (phospholipase C inhibitor) but not H89 (protein kinase A inhibitor). U-73122 or CI-988 inhibited the ability of CCK to cause phosphatidylinositol turnover and elevate cytosolic Ca2+. CI-988 or gefitinib inhibited the growth of NCI-H345 or H727 cells. CI-988 and gefitinib synergistically inhibited the growth of lung cancer cells. The results indicate that the CCK-BR regulates lung cancer proliferation in an EGFR-dependent mechanism through activation of Src, MMP and reactive oxygen species. Citation Format: Terry W. Moody, Suk Hee Lee, Paola Moreno Perez, Robert T Jensen. G-protein coupled receptors for cholecystokinin regulate transactivation of EGF receptors in lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2125. doi:10.1158/1538-7445.AM2014-2125