The nicotinic acetylcholine receptor-mediated reciprocal effects of the tobacco nitrosamine NNK and SLURP-1 on human mammary epithelial cells

Mina Kalantari-Dehaghi; Erinn A Parnell; Tara Armand; Hans-Ulrich Bernard; Sergei A Grando

doi:10.1016/j.intimp.2015.04.041

The nicotinic acetylcholine receptor-mediated reciprocal effects of the tobacco nitrosamine NNK and SLURP-1 on human mammary epithelial cells

Int Immunopharmacol. 2015 Nov;29(1):99-104. doi: 10.1016/j.intimp.2015.04.041. Epub 2015 May 15.

Authors

Mina Kalantari-Dehaghi¹, Erinn A Parnell², Tara Armand³, Hans-Ulrich Bernard⁴, Sergei A Grando⁵

Affiliations

¹ Department of Dermatology, University of California, Irvine, CA, USA.
² Department of Molecular Biology, University of California, Irvine, CA, USA; Division of Biomedical Sciences, University of California, Riverside, CA, USA.
³ Department of Molecular Biology, University of California, Irvine, CA, USA; Department of Bioengineering University of California, Berkeley, CA, USA.
⁴ Department of Molecular Biology, University of California, Irvine, CA, USA.
⁵ Department of Dermatology, University of California, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, CA, USA; Cancer Center and Research Institute, University of California, Irvine, CA, USA. Electronic address: sgrando@uci.edu.

PMID: 25986726
DOI: 10.1016/j.intimp.2015.04.041

Abstract

Recent research has demonstrated that the nicotinergic signaling network of mammary epithelium can both mediate the physiological control of normal breast epithelial cells (BECs) and exhibit tumor-promoting effects on malignant BECs. Therefore, mammary nicotinic acetylcholine (ACh) receptors (nAChRs) may become a specific target for novel anti-breast cancer therapies. Toward this goal, we investigated the difference in the ACh receptor repertoires between normal and malignant BECs, determined effects of nicotinic ligands on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-dependent activation of ERK1/2 and tumorigenic transformation of MCF10A cells, and characterized reciprocal effects of NNK and SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1)-1 on the expression of nAChR subunits and several oncogenes and tumor-suppressing genes in BECs. Both the non-malignant MCF10A and malignant MCF7 breast cells expressed α3, α5, α7, α9, α10, β1, β2, γ, δ and ε nAChR subunits and M(1), M(3), M(4) and M(5) muscarinic receptor subtypes. The malignancy was associated with expression of α1, α4 and β4 nAChR subunits and M(2) subtype. Malignant transformation of BECs was also associated with overexpression of α7-, and α9-made nAChRs. NNK upregulated ERK1/2 phosphorylation, stimulated expression of the gene encoding the tumor-promoter HGF, downregulated expression of the tumor suppressor gene CDKN2A, and induced tumorigenic transformation of MCF10A cells. Compared to the canonical nAChR antagonists, SLURP-1 showed the highest ability to abolish the nAChR-mediated effects of NNK in both cell-signaling and cell-transformation assays and reversed many effects of NNK on gene expression. SLURP-1 also markedly upregulated the tumor suppressor genes CDKN2B, RUNX3 and TP73. Altogether, the obtained results provided new insight into the molecular mechanisms of nAChR-mediated oncogenic effects of NNK on BECs and demonstrated the ability to abolish or reverse these effects by SLURP-1.

Keywords: Gene expression; MCF-10A cells; MCF-7 cells; NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone); Nicotinic acetylcholine receptors, proliferation, breast cancer; SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1)-1 and -2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Ly / genetics
Antigens, Ly / metabolism*
Breast Neoplasms / metabolism*
Cell Line, Tumor
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Gene Expression Regulation
Gene Expression Regulation, Enzymologic
Humans
Nitrosamines / pharmacology*
Phosphorylation
Receptors, Nicotinic / genetics
Receptors, Nicotinic / metabolism*
Up-Regulation
Urokinase-Type Plasminogen Activator / genetics
Urokinase-Type Plasminogen Activator / metabolism*

Substances

Antigens, Ly
Nitrosamines
Receptors, Nicotinic
SLURP1 protein, human
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
Extracellular Signal-Regulated MAP Kinases
Urokinase-Type Plasminogen Activator