Melatonin inhibits gallbladder cancer cell migration and invasion via ERK‑mediated induction of epithelial‑to‑mesenchymal transition

Tang,Hongwei; Shi,Xiaoyi; Zhu,Pengfei; Guo,Wenzhi; Li,Jie; Yan,Bing; Zhang,Shuijun

doi:10.3892/ol.2021.12870

Melatonin inhibits gallbladder cancer cell migration and invasion via ERK‑mediated induction of epithelial‑to‑mesenchymal transition

Authors:
- Hongwei Tang
- Xiaoyi Shi
- Pengfei Zhu
- Wenzhi Guo
- Jie Li
- Bing Yan
- Shuijun Zhang
View Affiliations

Affiliations: ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: June 15, 2021 https://doi.org/10.3892/ol.2021.12870
Article Number: 609
Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Melatonin is a naturally occurring molecule secreted by the pineal gland that exhibits antitumor properties and prevents the development of human cancer. However, little is known regarding the effects of melatonin on gallbladder cancer (GBC) cells. The present study aimed to investigate the role of melatonin on the prevention of GBC cell invasion. The GBC cell line, GBC‑SD, was treated with different concentrations of melatonin for different time periods, and the data indicated that melatonin markedly inhibited the invasion of GBC cells. Following treatment of GBC cells with melatonin, the protein levels of the epithelial marker, E‑cadherin, significantly increased, while the expression levels of the mesenchymal markers, N‑cadherin, Snail and vimentin, notably decreased. In addition, melatonin inhibited the phosphorylation of ERK1/2. Following treatment of the cells with the ERK activator, tert‑Butylhydroquinone, the anti‑invasive effects of melatonin were reversed by rescuing epithelial‑to‑mesenchymal transition in GBC cells. Taken together, these results suggest that melatonin inhibits GBC invasiveness by blocking the ERK signaling pathway. Thus, melatonin may be used as a potential novel cancer therapeutic drug for the treatment of GBC.

View Figures

View References

1	Misra S, Chaturvedi A, Misra NC and Sharma ID: Carcinoma of the gallbladder. Lancet Oncol. 4:167–176. 2003. View Article : Google Scholar : PubMed/NCBI
2	Hundal R and Shaffer EA: Gallbladder cancer: Epidemiology and outcome. Clin Epidemiol. 6:99–109. 2014.PubMed/NCBI
3	Sharma A, Sharma KL, Gupta A, Yadav A and Kumar A: Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol. 23:3978–3998. 2017. View Article : Google Scholar : PubMed/NCBI
4	Andia ME, Hsing AW, Andreotti G and Ferreccio C: Geographic variation of gallbladder cancer mortality and risk factors in chile: A population-based ecologic study. Int J Cancer. 123:1411–1416. 2008. View Article : Google Scholar : PubMed/NCBI
5	Sheth S, Bedford A and Chopra S: Primary gallbladder cancer: Recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol. 95:1402–1410. 2000. View Article : Google Scholar : PubMed/NCBI
6	Levy AD, Murakata LA and Rohrmann CA Jr: Gallbladder carcinoma: Radiologic-pathologic correlation. Radiographics. 21:295–314. 2001. View Article : Google Scholar : PubMed/NCBI
7	Cipolla-Neto J and Amaral FGD: Melatonin as a hormone: New physiological and clinical insights. Endocr Rev. 39:990–1028. 2018. View Article : Google Scholar : PubMed/NCBI
8	Bhattacharya S, Patel KK, Dehari D, Agrawal AK and Singh S: Melatonin and its ubiquitous anticancer effects. Mol Cell Biochem. 462:133–155. 2019. View Article : Google Scholar : PubMed/NCBI
9	Su SC, Hsieh MJ, Yang WE, Chung WH, Reiter RJ and Yang SF: Cancer metastasis: Mechanisms of inhibition by melatonin. J Pineal Res. 62:622017. View Article : Google Scholar
10	Wei JY, Li WM, Zhou LL, Lu QN and He W: Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation. J Pineal Res. 58:429–438. 2015. View Article : Google Scholar : PubMed/NCBI
11	Mao L, Dauchy RT, Blask DE, Dauchy EM, Slakey LM, Brimer S, Yuan L, Xiang S, Hauch A, Smith K, et al: Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma. J Pineal Res. 60:167–177. 2016. View Article : Google Scholar : PubMed/NCBI
12	Chao CC, Chen PC, Chiou PC, Hsu CJ, Liu PI, Yang YC, Reiter RJ, Yang SF and Tang CH: Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to twist. Clin Sci (Lond). 133:709–722. 2019. View Article : Google Scholar : PubMed/NCBI
13	Lin YW, Lee LM, Lee WJ, Chu CY, Tan P, Yang YC, Chen WY, Yang SF, Hsiao M and Chien MH: Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-κB DNA-binding activity. J Pineal Res. 60:277–290. 2016. View Article : Google Scholar : PubMed/NCBI
14	Mao L, Summers W, Xiang S, Yuan L, Dauchy RT, Reynolds A, Wren-Dail MA, Pointer D, Frasch T, Blask DE, et al: Melatonin represses metastasis in Her2-postive human breast cancer cells by suppressing RSK2 expression. Mol Cancer Res. 14:1159–1169. 2016. View Article : Google Scholar : PubMed/NCBI
15	Bubner B and Baldwin IT: Use of real-time PCR for determining copy number and zygosity in transgenic plants. Plant Cell Rep. 23:263–271. 2004. View Article : Google Scholar : PubMed/NCBI
16	Kumar R, Saneja A and Panda AK: An annexin V-FITC-propidium iodide-based method for detecting apoptosis in a non-small cell lung cancer cell line. Methods Mol Biol. 2279:213–223. 2021. View Article : Google Scholar : PubMed/NCBI
17	Faulstich H, Zobeley S, Rinnerthaler G and Small JV: Fluorescent phallotoxins as probes for filamentous actin. J Muscle Res Cell Motil. 9:370–383. 1988. View Article : Google Scholar : PubMed/NCBI
18	Hu H, Dong Z, Wang X, Bai L, Lei Q, Yang J, Li L, Li Q, Liu L, Zhang Y, et al: Dehydrocorydaline inhibits cell proliferation, migration and invasion via suppressing MEK1/2-ERK1/2 cascade in melanoma. Onco Targets Ther. 12:5163–5175. 2019. View Article : Google Scholar : PubMed/NCBI
19	Shi H, Bi H, Sun X, Dong H, Jiang Y, Mu H, Liu G, Kong W, Gao R and Su J: Antitumor effects of tubeimoside-1 in NCI-H1299 cells are mediated by microRNA-126-5p-induced inactivation of VEGF-A/VEGFR-2/ERK signaling pathway. Mol Med Rep. 17:4327–4336. 2018.PubMed/NCBI
20	Yu R, Tan TH and Kong AN: Butylated hydroxyanisole and its metabolite tert-butylhydroquinone differentially regulate mitogen-activated protein kinases. The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants. J Biol Chem. 14:28962–28970. 1997. View Article : Google Scholar : PubMed/NCBI
21	Baiu I and Visser B: Gallbladder cancer. JAMA. 320:12942018. View Article : Google Scholar : PubMed/NCBI
22	Wang J, Hao H, Yao L, Zhang X, Zhao S, Ling EA, Hao A and Li G: Melatonin suppresses migration and invasion via inhibition of oxidative stress pathway in glioma cells. J Pineal Res. 53:180–187. 2012. View Article : Google Scholar : PubMed/NCBI
23	Farriol M, Venereo Y, Orta X, Castellanos JM and Segovia-Silvestre T: In vitro effects of melatonin on cell proliferation in a colon adenocarcinoma line. J Appl Toxicol. 20:21–24. 2000. View Article : Google Scholar : PubMed/NCBI
24	Papazisis KT, Kouretas D, Geromichalos GD, Sivridis E, Tsekreli OK, Dimitriadis KA and Kortsaris AH: Effects of melatonin on proliferation of cancer cell lines. J Pineal Res. 25:211–218. 1998. View Article : Google Scholar : PubMed/NCBI
25	Petranka J, Baldwin W, Biermann J, Jayadev S, Barrett JC and Murphy E: The oncostatic action of melatonin in an ovarian carcinoma cell line. J Pineal Res. 26:129–136. 1999. View Article : Google Scholar : PubMed/NCBI
26	Ordoñez R, Carbajo-Pescador S, Prieto-Dominguez N, García-Palomo A, González-Gallego J and Mauriz JL: Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells. J Pineal Res. 56:20–30. 2014. View Article : Google Scholar
27	Cutando A, López-Valverde A, Arias-Santiago S, DE Vicente J and DE Diego RG: Role of melatonin in cancer treatment. Anticancer Res. 32:2747–2753. 2012.PubMed/NCBI
28	Nordlund JJ and Lerner AB: The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. 45:768–774. 1977. View Article : Google Scholar : PubMed/NCBI
29	Malhotra S, Sawhney G and Pandhi P: The therapeutic potential of melatonin: A review of the science. MedGenMed. 3:462004.PubMed/NCBI
30	Yerneni LK and Jayaraman S: Pharmacological action of high doses of melatonin on B16 murine melanoma cells depends on cell number at time of exposure. Melanoma Res. 13:113–117. 2003. View Article : Google Scholar : PubMed/NCBI
31	Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP and Olcese J: International union of basic and clinical pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 62:343–380. 2010. View Article : Google Scholar : PubMed/NCBI
32	Juszczak M, Roszczyk M, Kowalczyk E and Stempniak B: The influence od melatonin receptors antagonists, luzindole and 4-phenyl-2-propionamidotetralin (4-P-PDOT), on melatonin-dependent vasopressin and adrenocorticotropic hormone (ACTH) release from the rat hypothalamo-hypophysial system. In vitro and in vivo studies. J Physiol Pharmacol. 65:777–784. 2014.PubMed/NCBI
33	Baum B, Settleman J and Quinlan MP: Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol. 19:294–308. 2008. View Article : Google Scholar : PubMed/NCBI
34	Chen T, You Y, Jiang H and Wang ZZ: Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol. 232:3261–3272. 2017. View Article : Google Scholar : PubMed/NCBI
35	Zeisberg M and Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 119:1429–1437. 2009. View Article : Google Scholar : PubMed/NCBI
36	Xu S, Zhan M and Wang J: Epithelial-to-mesenchymal transition in gallbladder cancer: From clinical evidence to cellular regulatory networks. Cell Death Discov. 3:170692017. View Article : Google Scholar : PubMed/NCBI
37	Puhalla H, Herberger B, Soleiman A, Filipits M, Laengle F, Gruenberger T and Wrba F: E-cadherin and beta-catenin expression in normal, inflamed and cancerous gallbladder tissue. Anticancer Res. 25:4249–4254. 2005.PubMed/NCBI
38	Kai K, Masuda M and Aishima S: Inverse correlation between CD8⁺ inflammatory cells and E-cadherin expression in gallbladder cancer: Tissue microarray and imaging analysis. World J Clin Cases. 5:1–8. 2017. View Article : Google Scholar : PubMed/NCBI
39	Dong P, He XW, Gu J, Wu WG, Li ML, Yang JH, Zhang L, Ding QC, Lu JH, Mu JS, et al: Vimentin significantly promoted gallbladder carcinoma metastasis. Chin Med J (Engl). 124:4236–4244. 2011.PubMed/NCBI
40	Lee DG, Lee SH, Kim JS, Park J, Cho YL, Kim KS, Jo DY, Song IC, Kim N, Yun HJ, et al: Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression. J Hepatol. 63:1429–1439. 2015. View Article : Google Scholar : PubMed/NCBI
41	Acloque H, Adams MS, Fishwick K, Bronner-Fraser M and Nieto MA: Epithelial-mesenchymal transitions: The importance of changing cell state in development and disease. J Clin Invest. 119:1438–1449. 2009. View Article : Google Scholar : PubMed/NCBI
42	Buchegger K, Silva R, López J, Ili C, Araya JC, Leal P, Brebi P, Riquelme I and Roa JC: The ERK/MAPK pathway is overexpressed and activated in gallbladder cancer. Pathol Res Pract. 213:476–482. 2017. View Article : Google Scholar : PubMed/NCBI
43	Lu KH, Su SC, Lin CW, Hsieh YH, Lin YC, Chien MH, Reiter RJ and Yang SF: Melatonin attenuates osteosarcoma cell invasion by suppression of C-C motif chemokine ligand 24 through inhibition of the c-Jun N-terminal kinase pathway. J Pineal Res. 65:e125072018. View Article : Google Scholar : PubMed/NCBI