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Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way

  • Authors:
    • Chun Zhang
    • Ping Yu
    • Liang Zhu
    • Qingnan Zhao
    • Xiaotong Lu
    • Shuhong Bo
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 3309-3318
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    Published online on: October 2, 2017
       https://doi.org/10.3892/or.2017.6014
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Abstract

Nicotine can stimulate the progression of non-small cell lung cancer (NSCLC) through nicotinic acetylcholine receptors (nAChRs). The persistent proliferation of cancer cells is one of the key effects of nicotinic signaling. The present study aimed to clarify the mechanism of nicotine-induced proliferation in NSCLCs at the receptor subtype level. We have previously reported that there are various subtypes of nicotinic receptors expressed in NSCLC cell lines. In the present study, we demonstrated that blocking α7nAChRs agonized by nicotine could suppress the proliferation of H1299 cells in vitro and decrease H1299 tumor xenograft growth in nude mice. During this process, the expression of vimentin was also markedly attenuated, concomitant with the decreased expression of α7nAChR. These results were ascertained by knocking down the α7nAChR gene to abolish receptor functioning. Furthermore, under the stimulation of nicotine, the MEK/ERK signaling pathway was found to be inhibited when cells were treated with an antagonist of α7nAChR or an inhibitor of MEK. Collectively the results indicate that the changes in proliferation and vimentin expression of H1299 cells in response to α7nAChR stimulation are mediated by the MEK/ERK pathway. These findings demonstrate that α7nAChR plays an important role in H1299 cell proliferation, tumor growth and expression of vimentin. Therefore, blocking α7nAChRs in NSCLC may be a potential adjuvant therapy for the targeted treatment of NSCLC.
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1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Engström W, Darbre P, Eriksson S, Gulliver L, Hultman T, Karamouzis MV, Klaunig JE, Mehta R, Moorwood K, Sanderson T, et al: The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. Carcinogenesis. 36 Suppl 1:S38–S60. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Zhang C, Ding XP, Zhao QN, Yang XJ, An SM, Wang H, Xu L, Zhu L and Chen HZ: Role of α7-nicotinic acetylcholine receptor in nicotine-induced invasion and epithelial-to-mesenchymal transition in human non-small cell lung cancer cells. Oncotarget. 7:59199–59208. 2016.PubMed/NCBI

6 

Davis R, Rizwani W, Banerjee S, Kovacs M, Haura E, Coppola D and Chellappan S: Nicotine promotes tumor growth and metastasis in mouse models of lung cancer. PLoS One. 4:e75242009. View Article : Google Scholar : PubMed/NCBI

7 

Zheng Y, Ritzenthaler JD, Roman J and Han S: Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression. Am J Respir Cell Mol Biol. 37:681–690. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Albuquerque EX, Pereira EF, Alkondon M and Rogers SW: Mammalian nicotinic acetylcholine receptors: From structure to function. Physiol Rev. 89:73–120. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Gong WY, Wu JF, Liu BJ, Zhang HY, Cao YX, Sun J, Lv YB, Wu X and Dong JC: Flavonoid components in Scutellaria baicalensis inhibit nicotine-induced proliferation, metastasis and lung cancer-associated inflammation in vitro. Int J Oncol. 44:1561–1570. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Paleari L, Negri E, Catassi A, Cilli M, Servent D, D'Angelillo R, Cesario A, Russo P and Fini M: Inhibition of nonneuronal alpha7-nicotinic receptor for lung cancer treatment. Am J Respir Crit Care Med. 179:1141–1150. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Medjber K, Freidja ML, Grelet S, Lorenzato M, Maouche K, Nawrocki-Raby B, Birembaut P, Polette M and Tournier JM: Role of nicotinic acetylcholine receptors in cell proliferation and tumour invasion in broncho-pulmonary carcinomas. Lung Cancer. 87:258–264. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Russo P, Del Bufalo A, Milic M, Salinaro G, Fini M and Cesario A: Cholinergic receptors as target for cancer therapy in a systems medicine perspective. Curr Mol Med. 14:1126–1138. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Havel LS, Kline ER, Salgueiro AM and Marcus AI: Vimentin regulates lung cancer cell adhesion through a VAV2-Rac1 pathway to control focal adhesion kinase activity. Oncogene. 34:1979–1990. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Liu CY, Lin HH, Tang MJ and Wang YK: Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation. Oncotarget. 6:15966–15983. 2015.PubMed/NCBI

15 

Kanamoto A, Ninomiya I, Harada S, Tsukada T, Okamoto K, Nakanuma S, Sakai S, Makino I, Kinoshita J, Hayashi H, et al: Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma. Int J Oncol. 49:1859–1869. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Satelli A and Li S: Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci. 68:3033–3046. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Lahat G, Zhu QS, Huang KL, Wang S, Bolshakov S, Liu J, Torres K, Langley RR, Lazar AJ, Hung MC, et al: Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies. PLoS One. 5:e101052010. View Article : Google Scholar : PubMed/NCBI

18 

Tang JS, Xie BX, Bian XL, Xue Y, Wei NN, Zhou JH, Hao YC, Li G, Zhang LR and Wang KW: Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B. Acta Pharmacol Sin. 36:800–812. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Si ML, Long C, Chen MF and Lee TJ: Estrogen prevents β-amyloid inhibition of sympathetic α7-nAChR-mediated nitrergic neurogenic dilation in porcine basilar arteries. Acta Physiol. 203:13–23. 2011. View Article : Google Scholar

20 

Dasgupta P, Rastogi S, Pillai S, Orcarried Outz-Ercan D, Morris M, Haura E and Chellappan S: Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. J Clin Invest. 116:2208–2217. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Paleari L, Trombino S, Falugi C, Gallus L, Carlone S, Angelini C, Sepcic K, Turk T, Faimali M, Noonan DM, et al: Marine sponge-derived polymeric alkylpyridinium salts as a novel tumor chemotherapeutic targeting the cholinergic system in lung tumors. Int J Oncol. 29:1381–1388. 2006.PubMed/NCBI

22 

Sheppard BJ, Williams M, Plummer HK and Schuller HM: Activation of voltage-operated Ca2+-channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Int J Oncol. 16:513–518. 2000.PubMed/NCBI

23 

Zhou Y, Liao Q, Han Y, Chen J, Liu Z, Ling H, Zhang J, Yang W, Oyang L, Xia L, et al: Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small cell lung cancer. J Cancer. 7:2100–2109. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Lee CH, Wu CH and Ho YS: From smoking to cancers: Novel targets to neuronal nicotinic acetylcholine receptors. J Oncol. 2011:6934242011. View Article : Google Scholar : PubMed/NCBI

25 

Dasgupta P, Rizwani W, Pillai S, Kinkade R, Kovacs M, Rastogi S, Banerjee S, Carless M, Kim E, Coppola D, et al: Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. Int J Cancer. 124:36–45. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Boo HJ, Min HY, Jang HJ, Yun HJ, Smith JK, Jin Q, Lee HJ, Liu D, Kweon HS, Behrens C, et al: The tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells. Nat Commun. 7:129612016. View Article : Google Scholar : PubMed/NCBI

27 

Zhao Y: The oncogenic functions of nicotinic acetylcholine receptors. J Oncol. 2016:96504812016. View Article : Google Scholar : PubMed/NCBI

28 

Cardinale A, Nastrucci C, Cesario A and Russo P: Nicotine: Specific role in angiogenesis, proliferation and apoptosis. Crit Rev Toxicol. 42:68–89. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Improgo MR, Soll LG, Tapper AR and Gardner PD: Nicotinic acetylcholine receptors mediate lung cancer growth. Front Physiol. 4:2512013. View Article : Google Scholar : PubMed/NCBI

30 

Maouche K, Polette M, Jolly T, Medjber K, Cloëz-Tayarani I, Changeux JP, Burlet H, Terryn C, Coraux C, Zahm JM, et al: {alpha}7 nicotinic acetylcholine receptor regulates airway epithelium differentiation by controlling basal cell proliferation. Am J Pathol. 175:1868–1882. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Mendez MG, Kojima S and Goldman RD: Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 24:1838–1851. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Lanier MH, Kim T and Cooper JA: CARMIL2 is a novel molecular connection between vimentin and actin essential for cell migration and invadopodia formation. Mol Biol Cell. 26:4577–4588. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Vyas AR and Singh SV: Functional relevance of D,L-sulforaphane-mediated induction of vimentin and plasminogen activator inhibitor-1 in human prostate cancer cells. Eur J Nutr. 53:843–852. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Pérez-Sala D, Oeste CL, Martínez AE, Carrasco MJ, Garzón B and Cañada FJ: Vimentin filament organization and stress sensing depend on its single cysteine residue and zinc binding. Nat Commun. 6:72872015. View Article : Google Scholar : PubMed/NCBI

35 

Schaal C and Chellappan SP: Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers. Mol Cancer Res. 12:14–23. 2014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhang C, Yu P, Zhu L, Zhao Q, Lu X and Bo S: Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way. Oncol Rep 38: 3309-3318, 2017.
APA
Zhang, C., Yu, P., Zhu, L., Zhao, Q., Lu, X., & Bo, S. (2017). Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way. Oncology Reports, 38, 3309-3318. https://doi.org/10.3892/or.2017.6014
MLA
Zhang, C., Yu, P., Zhu, L., Zhao, Q., Lu, X., Bo, S."Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way". Oncology Reports 38.6 (2017): 3309-3318.
Chicago
Zhang, C., Yu, P., Zhu, L., Zhao, Q., Lu, X., Bo, S."Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way". Oncology Reports 38, no. 6 (2017): 3309-3318. https://doi.org/10.3892/or.2017.6014
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang C, Yu P, Zhu L, Zhao Q, Lu X and Bo S: Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way. Oncol Rep 38: 3309-3318, 2017.
APA
Zhang, C., Yu, P., Zhu, L., Zhao, Q., Lu, X., & Bo, S. (2017). Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way. Oncology Reports, 38, 3309-3318. https://doi.org/10.3892/or.2017.6014
MLA
Zhang, C., Yu, P., Zhu, L., Zhao, Q., Lu, X., Bo, S."Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way". Oncology Reports 38.6 (2017): 3309-3318.
Chicago
Zhang, C., Yu, P., Zhu, L., Zhao, Q., Lu, X., Bo, S."Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way". Oncology Reports 38, no. 6 (2017): 3309-3318. https://doi.org/10.3892/or.2017.6014
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