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NNK activates ERK1/2 and CREB/ATF‐1 via β‐1‐AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells
Author(s) -
E. Laag,
M. Majidi,
M. Cekanova,
T. Masi,
T. Takahashi,
H.M. Schuller
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21987
Subject(s) - creb , cancer research , signal transduction , chemistry , epidermal growth factor receptor , downregulation and upregulation , phosphorylation , biology , microbiology and biotechnology , endocrinology , receptor , transcription factor , biochemistry , gene
We have shown that the tobacco nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is an agonist for β‐adrenergic receptors (β‐ARs) and increased DNA synthesis of human lung adenocarinoma cells with features of bronchiolar Clara cells by binding to these receptors. Using a cell line derived from a human pulmonary adenocarcinoma with Clara cell phenotype (PACC) and immortalized human small airway epithelial cells (HPLD1), the putative cells of origin of this cancer type, our current studies have analyzed signaling initiated by binding of NNK to the β 1 ‐AR. NNK upregulated ERK1/2 and CREB/ATF‐1 phosphorylation in a PKA‐dependent manner in both cell lines. This response was further increased by transient overexpression of the β 1 ‐AR. Pre‐exposure of cells to the selective β 1 ‐AR antagonist, atenolol, attenuated the stimulatory effects of NNK, suggesting the latter upregulated ERK1/2 and CREB/ATF‐1 via this receptor. In vivo labeling and immunoprecipitation assays revealed that NNK phosphorylated the epidermal growth factor receptor (EGFR) at tyrosine residues, 991, 1068 and 1173, an effect inhibited by atenolol. The inhibitor of EGFR‐specific tyrosine kinases, AG1478, reduced NNK ability to stimulate ERK1/2 and CREB/ATF‐1. Genomic analysis of the exons 18–21 of the EGFR genes showed that no mutations were present in either gene. Collectively, our data provide evidence, for the first time, that NNK targets ERK1/2 and CREB/ATF‐1 proteins via dual signaling involving β 1 ‐AR and EGFR pathways in PACCs and their putative cells of origin. © 2006 Wiley‐Liss, Inc.