Mechanisms of tumor-promoting activities of nicotine in lung cancer: synergistic effects of cell membrane and mitochondrial nicotinic acetylcholine receptors

BMC Cancer

Sergei A Grando²  Valentin Galitovkiy¹  Igor B Shchepotin³  Alex I Chernyavsky¹ 

[1]Department of Dermatology, University of California, 134 Sprague Hall, Irvine 92697, CA, USA

[2]Cancer Center and Research Institute, University of California, 134 Sprague Hall, Irvine 92697, CA, USA

[3]National Cancer Institute, Kiev, Ukraine

关键词: Mitochondria;    Intrinsic apoptosis;    Growth factors;    Proliferation;    Nicotinic acetylcholine receptors;    Lung cancer cells;    Bronchial epithelial cells;   

Others  :  1143812
DOI  :  10.1186/s12885-015-1158-4

 received in 2014-11-07, accepted in 2015-03-04,  发布年份 2015

【 摘 要 】

Background

One of the major controversies of contemporary medicine is created by an increased consumption of nicotine and growing evidence of its connection to cancer, which urges elucidation of the molecular mechanisms of oncogenic effects of inhaled nicotine. Current research indicates that nicotinergic regulation of cell survival and death is more complex than originally thought, because it involves signals emanating from both cell membrane (cm)- and mitochondrial (mt)-nicotinic acetylcholine receptors (nAChRs). In this study, we elaborated on the novel concept linking cm-nAChRs to growth promotion of lung cancer cells through cooperation with the growth factor signaling, and mt-nAChRs — to inhibition of intrinsic apoptosis through prevention of opening of mitochondrial permeability transition pore (mPTP).

Methods

Experiments were performed with normal human lobar bronchial epithelial cells, the lung squamous cell carcinoma line SW900, and intact and NNK-transformed immortalized human bronchial cell line BEP2D.

Results

We demonstrated that the growth-promoting effect of nicotine mediated by activation of α7 cm-nAChR synergizes mainly with that of epidermal growth factor (EGF), α3 — vascular endothelial growth factor (VEGF), α4 — insulin-like growth factor I (IGF-I) and VEGF, whereas α9 with EGF, IGF-I and VEGF. We also established the ligand-binding abilities of mt-nAChRs and demonstrated that quantity of the mt-nAChRs coupled to inhibition of mPTP opening increases upon malignant transformation.

Conclusions

These results indicated that the biological sum of simultaneous activation of cm- and mt-nAChRs produces a combination of growth-promoting and anti-apoptotic signals that implement the tumor-promoting action of nicotine on lung cells. Therefore, nAChRs may be a promising molecular target to arrest lung cancer progression and re-open mitochondrial apoptotic pathways.

【 授权许可】

   
2015 Chernyavsky et al.; licensee BioMed Central.

【 图 表 】

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