Glutathione S‑transferase A1 mediates nicotine‑induced lung cancer cell metastasis by promoting epithelial‑mesenchymal transition

Wang,Wei; Liu,Feiyu; Wang,Chaoyang; Wang,Chengde; Tang,Yijun; Jiang,Zhongmin

doi:10.3892/etm.2017.4663

Glutathione S‑transferase A1 mediates nicotine‑induced lung cancer cell metastasis by promoting epithelial‑mesenchymal transition

Authors:
- Wei Wang
- Feiyu Liu
- Chaoyang Wang
- Chengde Wang
- Yijun Tang
- Zhongmin Jiang
View Affiliations

Affiliations: Department of Thoracic Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong 264000, P.R. China, Department of Pharmacy, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong 264000, P.R. China, Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
Published online on: June 23, 2017 https://doi.org/10.3892/etm.2017.4663
Pages: 1783-1788

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate the effect of glutathione S-transferase A1 (GSTA1) on lung cancer cell viability, invasion and adhesion in the presence of nicotine in vitro. Furthermore, the effect of GSTA1 on the epithelial-mesenchymal transition (EMT), a process strongly associated with lung cancer metastasis, was examined. Human lung carcinoma A549 cells were treated with various concentrations of nicotine (0.01, 0.1, 1 and 10 µM) and levels of GSTA1 mRNA and protein were measured by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. To knock down GSTA1 expression, GSTA1‑small interfering RNA was transfected into A549 cells. Cell viability, invasion and adhesion abilities were determined by MTT, Transwell‑Matrigel invasion and cell adhesion assays, respectively. The expression of the epithelial cell markers E‑cadherin and keratin, and the mesenchymal cell markers vimentin and N‑cadherin in A549 cells were examined by western blot analysis. The current study indicated that the expression of GSTA1 was increased in A549 cells following nicotine treatment. GSTA1 suppression inhibited the viability, invasion and adhesion of lung cancer cells. In addition, the increase in lung cancer cell viability, invasion and adhesion by nicotine was suppressed following GSTA1 knockdown. Furthermore, GSTA1 affected the expression of EMT markers in nicotine‑treated or untreated lung cancer cells. Thus the present study demonstrates that GSTA1 promotes lung cancer cell invasion and adhesion and mediates the effect of nicotine on lung cancer cell metastasis in vitro. Furthermore, the results demonstrated that GSTA1 exerts its effect on lung cancer cell metastasis by promoting the EMT.

View Figures

View References

1	Torre LA, Siegel RL and Jemal A: Lung Cancer Statistics. Adv Exp Med Biol. 893:1–19. 2016. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar : PubMed/NCBI
3	Nguyen DX, Bos PD and Massagué J: Metastasis: From dissemination to organ-specific colonization. Nat Rev Cancer. 9:274–284. 2009. View Article : Google Scholar : PubMed/NCBI
4	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
5	Chambers AF, Groom AC and MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2:563–572. 2002. View Article : Google Scholar : PubMed/NCBI
6	Fidler IJ: The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3:453–458. 2003. View Article : Google Scholar : PubMed/NCBI
7	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
8	Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A and Kirchner T: Invasion and metastasis in colorectal cancer: Epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs. 179:56–65. 2005. View Article : Google Scholar : PubMed/NCBI
9	Hayes JD, Flanagan JU and Jowsey IR: Glutathione transferases. Annu Rev Pharmacol Toxicol. 45:51–88. 2005. View Article : Google Scholar : PubMed/NCBI
10	Khan MS, Khan MK, Siddiqui MH and Arif JM: An in vivo and in silico approach to elucidate the tocotrienol-mediated fortification against infection and inflammation induced alterations in antioxidant defense system. Eur Rev Med Pharmacol Sci. 15:916–930. 2011.PubMed/NCBI
11	Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, Hsieh WS, Isaacs WB and Nelson WG: Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci USA. 91:pp. 11733–11737. 1994; View Article : Google Scholar : PubMed/NCBI
12	Niu D, Zhang J, Ren Y, Feng H and Chen WN: HBx genotype D represses GSTP1 expression and increases the oxidative level and apoptosis in HepG2 cells. Mol Oncol. 3:67–76. 2009. View Article : Google Scholar : PubMed/NCBI
13	Zhang YJ, Chen Y, Ahsan H, Lunn RM, Chen SY, Lee PH, Chen CJ and Santella RM: Silencing of glutathione S-transferase P1 by promoter hypermethylation and its relationship to environmental chemical carcinogens in hepatocellular carcinoma. Cancer Lett. 221:135–143. 2005. View Article : Google Scholar : PubMed/NCBI
14	Reszka E, Wasowicz W and Gromadzinska J: Genetic polymorphism of xenobiotic metabolising enzymes, diet and cancer susceptibility. Br J Nutr. 96:609–619. 2006.PubMed/NCBI
15	Pan XD, Yang ZP, Tang QL, Peng T, Zhang ZB, Zhou SG, Wang GX, He B and Zang LQ: Expression and function of GSTA1 in lung cancer cells. Asian Pac J Cancer Prev. 15:8631–8635. 2014. View Article : Google Scholar : PubMed/NCBI
16	Hecht SS: Cigarette smoking: Cancer risks, carcinogens, and mechanisms. Langenbecks Arch Surg. 391:603–613. 2006. View Article : Google Scholar : PubMed/NCBI
17	Guingab-Cagmat J, Bauzo RM, Bruijnzeel AW, Wang KK, Gold MS and Kobeissy FH: Methods in tobacco abuse: Proteomic changes following second-hand smoke exposure. Methods Mol Biol. 829:329–348. 2012. View Article : Google Scholar : PubMed/NCBI
18	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
19	Grozio A, Catassi A, Cavalieri Z, Paleari L, Cesario A and Russo P: Nicotine, lung and cancer. Anticancer Agents Med Chem. 7:461–466. 2007. View Article : Google Scholar : PubMed/NCBI
20	Cattaneo MG, Codignola A, Vicentini LM, Clementi F and Sher E: Nicotine stimulates a serotonergic autocrine loop in human small-cell lung carcinoma. Cancer Res. 53:5566–5568. 1993.PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Vos RM and Van Bladeren PJ: Glutathione S-transferases in relation to their role in the biotransformation of xenobiotics. Chem Biol Interact. 75:241–265. 1990. View Article : Google Scholar : PubMed/NCBI
23	Watson MA, Stewart RK, Smith GB, Massey TE and Bell DA: Human glutathione S-transferase P1 polymorphisms: Relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis. 19:275–280. 1998. View Article : Google Scholar : PubMed/NCBI
24	Stoehlmacher J, Park DJ, Zhang W, Groshen S, Tsao-Wei DD, Yu MC and Lenz HJ: Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst. 94:936–942. 2002. View Article : Google Scholar : PubMed/NCBI
25	Howells RE, Dhar KK, Hoban PR, Jones PW, Fryer AA, Redman CW and Strange RC: Association between glutathione-S-transferase GSTP1 genotypes, GSTP1 over-expression, and outcome in epithelial ovarian cancer. Int J Gynecol Cancer. 14:242–250. 2004. View Article : Google Scholar : PubMed/NCBI
26	Wenzlaff AS, Cote ML, Bock CH, Land SJ and Schwartz AG: GSTM1, GSTT1 and GSTP1 polymorphisms, environmental tobacco smoke exposure and risk of lung cancer among never smokers: A population-based study. Carcinogenesis. 26:395–401. 2005. View Article : Google Scholar : PubMed/NCBI
27	White DL, Li D, Nurgalieva Z and El-Serag HB: Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: A HuGE systematic review and meta-analysis. Am J Epidemiol. 167:377–389. 2008. View Article : Google Scholar : PubMed/NCBI
28	Kilburn L, Okcu MF, Wang T, Cao Y, Renfro-Spelman A, Aldape KD, Gilbert MR and Bondy M: Glutathione S-transferase polymorphisms are associated with survival in anaplastic glioma patients. Cancer. 116:2242–2249. 2010.PubMed/NCBI
29	Sergentanis TN and Economopoulos KP: GSTT1 and GSTP1 polymorphisms and breast cancer risk: A meta-analysis. Breast Cancer Res Treat. 121:195–202. 2010. View Article : Google Scholar : PubMed/NCBI
30	Xu Z, Zhu H, Luk JM, Wu D, Gu D, Gong W, Tan Y, Zhou J, Tang J, Zhang Z, et al: Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer. Cancer. 118:5489–5496. 2012. View Article : Google Scholar : PubMed/NCBI
31	Sharma A, Patrick B, Li J, Sharma R, Jeyabal PV, Reddy PM, Awasthi S and Awasthi YC: Glutathione S-transferases as antioxidant enzymes: Small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis. Arch Biochem Biophys. 452:165–173. 2006. View Article : Google Scholar : PubMed/NCBI
32	Yang Y, Sharma R, Sharma A, Awasthi S and Awasthi YC: Lipid peroxidation and cell cycle signaling: 4-hydroxynonenal, a key molecule in stress mediated signaling. Acta Biochim Pol. 50:319–336. 2003.PubMed/NCBI
33	Cheng JZ, Singhal SS, Sharma A, Saini M, Yang Y, Awasthi S, Zimniak P and Awasthi YC: Transfection of mGSTA4 in HL-60 cells protects against 4-hydroxynonenal-induced apoptosis by inhibiting JNK-mediated signaling. Arch Biochem Biophys. 392:197–207. 2001. View Article : Google Scholar : PubMed/NCBI
34	Zhao T, Singhal SS, Piper JT, Cheng J, Pandya U, Clark-Wronski J, Awasthi S and Awasthi YC: The role of human glutathione S-transferases hGSTA1-1 and hGSTA2-2 in protection against oxidative stress. Arch Biochem Biophys. 367:216–224. 1999. View Article : Google Scholar : PubMed/NCBI
35	Adnan H, Quach H, MacIntosh K, Antenos M and Kirby GM: Low levels of GSTA1 expression are required for Caco-2 cell proliferation. PLoS One. 7:e517392012. View Article : Google Scholar : PubMed/NCBI
36	Egleton RD, Brown KC and Dasgupta P: Nicotinic acetylcholine receptors in cancer: Multiple roles in proliferation and inhibition of apoptosis. Trends Pharmacol Sci. 29:151–158. 2008. View Article : Google Scholar : PubMed/NCBI
37	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
38	Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL and Cooke JP: Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 7:833–839. 2001. View Article : Google Scholar : PubMed/NCBI
39	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
40	Lim J and Thiery JP: Epithelial-mesenchymal transitions: Insights from development. Development. 139:3471–3486. 2012. View Article : Google Scholar : PubMed/NCBI
41	Hay ED and Zuk A: Transformations between epithelium and mesenchyme: Normal, pathological, and experimentally induced. Am J Kidney Dis. 26:678–690. 1995. View Article : Google Scholar : PubMed/NCBI
42	Patel NA, Patel PS and Vora HH: Role of PRL-3, Snail, Cytokeratin and Vimentin expression in epithelial mesenchymal transition in breast carcinoma. Breast Dis. 35:113–127. 2015. View Article : Google Scholar : PubMed/NCBI
43	Zeisberg M and Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 119:1429–1437. 2009. View Article : Google Scholar : PubMed/NCBI
44	Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW and Waltham M: Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tissues Organs. 185:191–203. 2007. View Article : Google Scholar : PubMed/NCBI