Reciprocal effects of NNK and SLURP-1 on oncogene expression in target epithelial cells

• Published in: Life sciences (1973) 2012-11, Vol.91 (21-22), p.1122-1125
• Main Authors: Kalantari-Dehaghi, Mina, Bernard, Hans-Ulrich, Grando, Sergei A.
• Format: Article
• Language: English
• Subjects: adhesion; Antigens, Ly - metabolism; apoptosis; BEP2D cells; Bronchi - cytology; Bronchi - drug effects; Bronchi - metabolism; Bronchi - pathology; carcinogenicity; Carcinogens - metabolism; Cell Line, Tumor; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; cholinergic receptors; epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene expression; gene expression regulation; Gene Expression Regulation, Neoplastic - drug effects; growth factors; Head and neck cancers; Het-1A cells; Humans; Lung cancer; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mouth - cytology; Mouth - drug effects; Mouth - metabolism; Mouth - pathology; Mouth Neoplasms - chemically induced; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; neoplastic cell transformation; Nitrosamines - adverse effects; Nitrosamines - metabolism; NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone); oncogenes; plasminogen activator; SLURP-1 (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1); tobacco; transcription factors; tumor necrosis factors; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2012.02.004

To elucidate how the nicotinic acetylcholine receptors expressed on bronchial and oral epithelial cells targeted by the tobacco nitrosamine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) facilitate carcinogenic transformation. Since NNK-dependent transformation can be abolished by the nicotinergic secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1), we compared effects of NNK and recombinant (r)SLURP-1 on the expression of genes related to tumorigenesis in human immortalized bronchial and oral epithelial cell lines BEP2D and Het-1A, respectively. NNK stimulated expression of oncogenic genes, including MYB and PIK3CA in BEP2D, ETS1, NRAS and SRC in Het-1A, and AKT1, KIT and RB1 in both cell types, which could be abolished in the presence of rSLURP-1. Other cancer-related genes whose upregulation by NNK was abolishable by rSLURP-1 were the growth factors EGF in BEP2D cells and HGF in Het-1A cells, and the transcription factors CDKN2A and STAT3 (Het-1A only). NNK also upregulated the anti-apoptotic BCL2 (Het-1A) and downregulated the pro-apoptotic TNF (Het-1A), BAX and CASP8 (BEP2D), all of which could be abolished, in part, by rSLURP-1. NNK decreased expression of the CTNNB1 gene encoding the intercellular adhesion molecule β-catenin (BEP2D), as well as tumor suppressors CDKN3 and FOXD3 in BEP2D cells and SERPINB5 in Het-1A cells. These pro-oncogenic effects of NNK were abolished by rSLURP-1 that also upregulated RUNX3. The obtained results identified target genes for both NNK and SLURP-1 and shed light on the molecular mechanism of their reciprocal effects on tumorigenic transformation of bronchial and oral epithelial cells.