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Tumor Biology
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

Alpha 7-nicotinic acetylcholine receptor mediates the sensitivity of gastric cancer cells to 5-fluorouracil

Authors: Wei-Yu Chen, Chien-Yu Huang, Wan-Li Cheng, Chin-Sheng Hung, Ming-Te Huang, Cheng-Jeng Tai, Yen-Nien Liu, Chi-Long Chen, Yu-Jia Chang

Published in: Tumor Biology | Issue 12/2015

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Abstract

Gastric cancer is the second most common cause of cancer mortality worldwide. Most gastric cancer patients are asymptomatic until the advanced stages, for which current therapeutic treatments are suboptimal. 5-Fluorouracil (5-FU), an antimetabolite agent, is widely used in gastric cancer therapy. However, the presence of drug resistance in gastric cancer patients reduces the cytotoxic activity of 5-FU. In gastric cancer, no research has yet been conducted to analyze the effect of alpha 7-nicotinic acetylcholine receptor (A7-nAChR) on the therapeutic response to 5-FU. In this study, we generated A7-nAChR knockdown (A7-nAChR-KD) AGS cells by a small interfering RNA (siRNA) technique in gastric cancer cells. The anti-proliferative effects of 5-FU were determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, and cell cycle determination. We found that A7-nAChR-KD cells were more resistant to 5-FU treatment compared with the scrambled control cells according to the MTT assay. The apoptotic cell population was increased more in scrambled control cells treated with 5-FU than A7-nAChR-KD cells according to the cell cycle distribution and TUNEL assays. We analyzed expression levels of survival and apoptosis-associated proteins (pAkt, Akt, Mcl-1, Bcl-2, Bad, and Bax) altered by 5-FU treatment. Survival and antiapoptosis signaling (pAkt, Akt, Mcl-1 and Bcl-2) was downregulated, and the proapoptotic proteins (Bad and Bax) were upregulated in 5-FU-treated control cells but expression levels of Bcl-2, Bad, and Bad were not altered in 5-FU-treated A7-nAChR-KD cells. This is consistent with A7-nAChR-KD cells exhibiting more resistance to 5-FU treatment. In our study, we carried out an in vitro study on AGS gastric cancer cell line to elucidate the anticancer efficacy and molecular mechanisms of A7-nAChR silencing on 5-FU-induced cell death. The results clearly showed that depletion of A7-nAChR suppressed the drug sensitivity of gastric cancer cells to 5-FU treatment.
Literature
1.
2.
Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. CD004064.
3.
Mizuarai S, Yamanaka K, Kotani H. Mutant p53 induces the gef-h1 oncogene, a guanine nucleotide exchange factor-h1 for rhoa, resulting in accelerated cell proliferation in tumor cells. Cancer Res. 2006;66:6319–26.CrossRefPubMed
4.
Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–8.CrossRefPubMed
5.
Chu E, Callender MA, Farrell MP, Schmitz JC. Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol. 2003;52 Suppl 1:S80–9.CrossRefPubMed
6.
Vinod BS, Antony J, Nair HH, Puliyappadamba VT, Saikia M, Narayanan SS, et al. Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5-fluorouracil. Cell Death Dis. 2013;4:e505.CrossRefPubMedPubMedCentral
7.
8.
Tabuchi T, Ito Y, Ioka A, Nakayama T, Miyashiro I, Tsukuma H. Tobacco smoking and the risk of subsequent primary cancer among cancer survivors: a retrospective cohort study. Ann Oncol. 2013;24:2699–704.CrossRefPubMed
9.
Shen T, Le W, Yee A, Kamdar O, Hwang PH, Upadhyay D. Nicotine induces resistance to chemotherapy in nasal epithelial cancer. Am J Rhinol Allergy. 2010;24:e73–7.CrossRefPubMed
10.
Cucina A, Dinicola S, Coluccia P, Proietti S, D'Anselmi F, Pasqualato A, et al. Nicotine stimulates proliferation and inhibits apoptosis in colon cancer cell lines through activation of survival pathways. J Surg Res. 2012;178:233–41.CrossRefPubMed
11.
Dinicola S, Morini V, Coluccia P, Proietti S, D'Anselmi F, Pasqualato A, et al. Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs. Toxicol In Vitro. 2013;27:2256–63.CrossRefPubMed
12.
Chang YJ, Chiu CC, Wu CH, An J, Wu CC, Liu TZ, et al. Glucose-regulated protein 78 (grp78) silencing enhances cell migration but does not influence cell proliferation in hepatocellular carcinoma. Ann Surg Oncol. 2010;17:1703–9.CrossRefPubMed
13.
Chiou JF, Tai CJ, Huang MT, Wei PL, Wang YH, An J, et al. Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma. Ann Surg Oncol. 2010;17:603–12.CrossRefPubMed
14.
Lien YC, Wang W, Kuo LJ, Liu JJ, Wei PL, Ho YS, et al. Nicotine promotes cell migration through alpha7 nicotinic acetylcholine receptor in gastric cancer cells. Ann Surg Oncol. 2011;18:2671–9.CrossRefPubMed
15.
Wei PL, Chang YJ, Ho YS, Lee CH, Yang YY, An J, et al. Tobacco-specific carcinogen enhances colon cancer cell migration through alpha7-nicotinic acetylcholine receptor. Ann Surg. 2009;249:978–85.CrossRefPubMed
16.
Wei PL, Kuo LJ, Huang MT, Ting WC, Ho YS, Wang W, et al. Nicotine enhances colon cancer cell migration by induction of fibronectin. Ann Surg Oncol. 2011;18-1782-90.
17.
Wang SK, Liang PH, Astronomo RD, Hsu TL, Hsieh SL, Burton DR, et al. Targeting the carbohydrates on hiv-1: interaction of oligomannose dendrons with human monoclonal antibody 2g12 and dc-sign. Proc Natl Acad Sci U S A. 2008;105:3690–5.CrossRefPubMedPubMedCentral
18.
Sowinski S, Jolly C, Berninghausen O, Purbhoo MA, Chauveau A, Kohler K, et al. Membrane nanotubes physically connect t cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol. 2008;10:211–9.CrossRefPubMed
19.
McLean MH, El-Omar EM. Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014;11:664–74.CrossRefPubMed
20.
Ladeiras-Lopes R, Pereira AK, Nogueira A, Pinheiro-Torres T, Pinto I, Santos-Pereira R, et al. Smoking and gastric cancer: systematic review and meta-analysis of cohort studies. Cancer Causes Control. 2008;19:689–701.CrossRefPubMed
21.
Hecht SS, Carmella SG, Chen M, Dor Koch JF, Miller AT, Murphy SE, et al. Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation. Cancer Res. 1999;59:590–6.PubMed
22.
23.
Smedlund K, Tano JY, Margiotta J, Vazquez G. Evidence for operation of nicotinic and muscarinic acetylcholine receptor-dependent survival pathways in human coronary artery endothelial cells. J Cell Biochem. 2011;112:1978–84.CrossRefPubMed
24.
25.
Shin VY, Wu WK, Chu KM, Wong HP, Lam EK, Tai EK, et al. Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol Cancer Res. 2005;3:607–15.CrossRefPubMed
26.
Wang YY, Liu Y, Ni XY, Bai ZH, Chen QY, Zhang Y, et al. Nicotine promotes cell proliferation and induces resistance to cisplatin by α7 nicotinic acetylcholine receptor-mediated activation in Raw264.7 and E14 cells. Oncol Rep. 2014;31:1480–8.PubMed
27.
Guha P, Bandyopadhyaya G, Polumuri SK, Chumsri S, Gade P, Kalvakolanu DV, et al. Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin, α9 nicotinic acetylcholine receptor and STAT3. Breast Cancer Res Treat. 2014;145:5–22.CrossRefPubMedPubMedCentral
28.
Chen RJ, Ho YS, Guo HR, Wang YJ. Long-term nicotine exposure-induced chemoresistance is mediated by activation of Stat3 and downregulation of ERK1/2 via nAChR and beta-adrenoceptors in human bladder cancer cells. Toxicol Sci. 2010;115:118–30.CrossRefPubMed
29.
Trevino JG, Pillai S, Kunigai S, Singh S, Fulp WJ, Centeno BA, et al. Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreastic adenocarcinoma. Neoplasia. 2012;14:1102–14.CrossRefPubMedPubMedCentral
30.
Xian XS, Park H, Choi MG, Park JM. Cannabinoid receptor agonist as an alternative drug in 5-fluorouracil-resistant gastric cancer cells. Anticancer Res. 2013;33:2541–7.PubMed
31.
Florou AN, Gkiozos IC, Tsagouli SK, Souliotis KN, Syrigos KN. Clinical significance of smoking cessation in subjects with cancer: a 30-year review. Respir Care. 2014;59:1924–36.CrossRefPubMed
32.
Singh S, Pillai S, Chellappan S. Nicotinic acetylcholine receptor signaling in tumor growth and metastasis. J Oncol. 2011;456743.
33.
Warren GW, Sobus S, Gritz ER. The biological and clinical effects of smoking by patients with cancer and strategies to implement evidence-based tobacco cessation support. Lancet Oncol. 2014;15:e568–80.CrossRefPubMed
34.
Wessler I, Kirkpatrick CJ, Racke K. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in human. Pharmacol Ther. 1998;77:59–79.CrossRefPubMed
35.
Valiante S, Capaldo A, Virgilio F, Sciarrillo R, De Falco M, Gay F, et al. Distribution of α7 and α4 nicotinic acetylcholine receptor subunits in several tissues of Triturus carnifex (Amphibia, Urodela). Tissue Cell. 2004;36:391–8.CrossRefPubMed
36.
Wu CH, Lee CH, Ho YS. Nicotinic acetylcholine receptor-based blockade: applications of molecular targets for cancer therapy. Clin Cancer Res. 2011;17:3533–41.CrossRefPubMed
37.
Al-Wadei MH, Al-Wadei HA, Schuller HM. Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors alpha3, alpha5, and alpha7. Mol Cancer Res. 2012;10:239–49.CrossRefPubMed
38.
Murakami D, Tsujitani S, Osaki T, Saito H, Katano K, Tatebe S, et al. Expression of phosphorylated Akt (pAkt) in gastric carcinoma predicts prognosis and efficacy of chemotherapy. Gastric Cancer. 2007;10:45–51.CrossRefPubMed
39.
Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 2005;117:376–80.CrossRefPubMed
Metadata
Title
Alpha 7-nicotinic acetylcholine receptor mediates the sensitivity of gastric cancer cells to 5-fluorouracil
Authors
Wei-Yu Chen
Chien-Yu Huang
Wan-Li Cheng
Chin-Sheng Hung
Ming-Te Huang
Cheng-Jeng Tai
Yen-Nien Liu
Chi-Long Chen
Yu-Jia Chang
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3668-8

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