Melatonin treatment increases the transcription of cell proliferation-related genes prior to inducing cell death in C6 glioma cells in vitro

Qu,Jiagui; Rizak,Joshua  D.; Li,Xiaomiao; Li,Jiejing; Ma,Yuanye

doi:10.3892/ol.2013.1413

August 2013 Volume 6 Issue 2

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August 2013 Volume 6 Issue 2

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Article

Melatonin treatment increases the transcription of cell proliferation-related genes prior to inducing cell death in C6 glioma cells in vitro

Authors:
- Jiagui Qu
- Joshua D. Rizak
- Xiaomiao Li
- Jiejing Li
- Yuanye Ma
View Affiliations / Copyright

Affiliations: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China, State Key Laboratory of Brain and Cognitive Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P.R. China, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P.R. China, State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
Pages: 347-352
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Published online on: June 18, 2013

https://doi.org/10.3892/ol.2013.1413
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Abstract

A number of studies have suggested that melatonin possesses anticancer properties. However, conflicting data exists with regard to the role of melatonin in the treatment of cancer. In the present study, the effects of melatonin on the transcriptional regulation of three genes associated with cell proliferation (Nestin, Bmi-1 and Sox2), and on C6 glioma cell survival and viability, were investigated in vitro to evaluate the use of melatonin in cancer therapy. Melatonin was shown to increase the mRNA levels of Nestin, Bmi-1 and Sox2 in a similar pattern, with the highest mRNA levels noted at a concentration of 3 mM. At higher concentrations of melatonin (5 mM), the mRNA levels of Nestin, Bmi-1 and Sox2 were reduced from their peak levels, and were correlated with changes observed in immunofluorescence morphology studies, cell viability and survival assays. Immunofluorescence studies of Nestin-stained cells demonstrated that treatment with a higher concentration of melatonin (3 and 5 mM) led to the Nestin filaments condensing and rearranging around the cell nuclei, and an alteration in the cell morphology. C6 cell viability was also significantly decreased at 3 mM melatonin, and cell death was observed at 5 and 10 mM melatonin. These results suggested that Nestin, Bmi-1 and Sox2 were strongly correlated with the survival of C6 cells following treatment with melatonin, and that high therapeutic concentrations of melatonin (>5 mM) were required to induce cell death. These findings suggested that the implementation of melatonin in the treatment of glioma and other types of cancer may be inhibited by conflicting cell growth signals in cells. Therefore, adjunct therapy is required to improve the efficacy of melatonin in the treatment of cancer.

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1.	Sánchez-Hidalgo M, Guerrero JM, Villegas I, Packham G and de la Lastra CA: Melatonin, a natural programmed cell death inducer in cancer. Curr Med Chem. 19:3805–3821. 2012.PubMed/NCBI
2.	Tan DX, Reiter RJ, Manchester LC, et al: Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2:181–197. 2002. View Article : Google Scholar
3.	Chakravarty S and Rizvi SI: Circadian modulation of human erythrocyte plasma membrane redox system by melatonin. Neurosci Lett. 518:32–35. 2012. View Article : Google Scholar : PubMed/NCBI
4.	Reiter RJ: Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol. 56:359–384. 1998. View Article : Google Scholar : PubMed/NCBI
5.	Altun A and Ugur-Altun B: Melatonin: therapeutic and clinical utilization. Int J Clin Pract. 61:835–845. 2007. View Article : Google Scholar : PubMed/NCBI
6.	Wu YH and Swaab DF: The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res. 38:145–152. 2005.
7.	Mayo JC, Sainz RM, Tan DX, Antolín I, Rodríguez C and Reiter RJ: Melatonin and Parkinson’s disease. Endocrine. 27:169–178. 2005.
8.	Tamarkin L, Cohen M, Roselle D, Reichert C, Lippman M and Chabner B: Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res. 41:4432–4436. 1981.PubMed/NCBI
9.	Lissoni P, Meregalli S, Nosetto L, et al: Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 53:43–46. 1996. View Article : Google Scholar : PubMed/NCBI
10.	Wang J, Hao H, Yao L, et al: 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
11.	Martín V, Herrera F, Carrera-Gonzalez P, et al: Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res. 66:1081–1088. 2006.PubMed/NCBI
12.	Martín V, Herrera F, García-Santos G, et al: Involvement of protein kinase C in melatonin’s oncostatic effect in C6 glioma cells. J Pineal Res. 43:239–244. 2007.
13.	Vijayalaxmi, Reiter RJ, Tan DX, Herman TS and Thomas CR Jr: Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys. 59:639–653. 2004. View Article : Google Scholar : PubMed/NCBI
14.	Andrabi SA, Sayeed I, Siemen D, Wolf G and Horn TF: Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 18:869–871. 2004.PubMed/NCBI
15.	Radogna F, Paternoster L, Albertini MC, et al: Melatonin antagonizes apoptosis via receptor interaction in U937 monocytic cells. J Pineal Res. 43:154–162. 2007. View Article : Google Scholar : PubMed/NCBI
16.	Esposito E, Iacono A, Muià C, et al: Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res. 44:78–87. 2008.PubMed/NCBI
17.	Sharma R, Ottenhof T, Rzeczkowska PA and Niles LP: Epigenetic targets for melatonin: induction of histone H3 hyperacetylation and gene expression in C17.2 neural stem cells. J Pineal Res. 45:277–284. 2008. View Article : Google Scholar : PubMed/NCBI
18.	Matsuda M, Katoh-Semba R, Kitani H and Tomooka Y: A possible role of the nestin protein in the developing central nervous system in rat embryos. Brain Res. 723:177–189. 1996. View Article : Google Scholar : PubMed/NCBI
19.	Lendahl U, Zimmerman LB and McKay RD: CNS stem cells express a new class of intermediate filament protein. Cell. 60:585–595. 1990. View Article : Google Scholar : PubMed/NCBI
20.	Wan F, Herold-Mende C, Campos B, et al: Association of stem cell-related markers and survival in astrocytic gliomas. Biomarkers. 16:136–143. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Rushing EJ, Sandberg GD and Horkayne-Szakaly I: High-grade astrocytomas show increased Nestin and Wilms’s tumor gene (WT1) protein expression. Int J Surg Pathol. 18:255–259. 2010.PubMed/NCBI
22.	Zhang M, Song T, Yang L, et al: Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res. 27:852008. View Article : Google Scholar : PubMed/NCBI
23.	Rutka JT, Ivanchuk S, Mondal S, et al: Co-expression of nestin and vimentin intermediate filaments in invasive human astrocytoma cells. Int J Dev Neurosci. 17:503–515. 1999. View Article : Google Scholar : PubMed/NCBI
24.	Flørenes VA, Holm R, Myklebost O, Lendahl U and Fodstad O: Expression of the neuroectodermal intermediate filament nestin in human melanomas. Cancer Res. 54:354–356. 1994.PubMed/NCBI
25.	Contesso G, Mouriesse H, Friedman S, Genin J, Sarrazin D and Rouesse J: The importance of histologic grade in long-term prognosis of breast cancer: a study of 1,010 patients, uniformly treated at the Institut Gustave-Roussy. J Clin Oncol. 5:1378–1386. 1987.PubMed/NCBI
26.	Liu R, Wang X, Chen GY, et al: The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 356:217–226. 2007. View Article : Google Scholar : PubMed/NCBI
27.	van der Lugt NM, Domen J, Linders K, et al: Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 protooncogene. Genes Dev. 8:757–769. 1994.
28.	Episkopou V: SOX2 functions in adult neural stem cells. Trends Neurosci. 28:219–221. 2005. View Article : Google Scholar : PubMed/NCBI
29.	Papp B and Müller J: Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev. 20:2041–2054. 2006. View Article : Google Scholar : PubMed/NCBI
30.	Leung C, Lingbeek M, Shakhova O, et al: Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature. 428:337–341. 2004. View Article : Google Scholar : PubMed/NCBI
31.	Boyer LA, Lee TI, Cole MF, et al: Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 122:947–956. 2005. View Article : Google Scholar : PubMed/NCBI
32.	Yu CC, Lo WL, Chen YW, et al: Bmi-1 regulates snail expression and promotes metastasis ability in head and neck squamous cancer-derived ALDH1 positive cells. J Oncol. 2011:6092592011.PubMed/NCBI
33.	Song LB, Li J, Liao WT, et al: The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 119:3626–3636. 2009. View Article : Google Scholar
34.	Lu Y, Futtner C, Rock JR, et al: Evidence that SOX2 overexpression is oncogenic in the lung. PLoS One. 5:e110222010. View Article : Google Scholar : PubMed/NCBI
35.	Yang S, Zheng J, Ma Y, et al: Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy. Oncol Rep. 28:186–192. 2012.PubMed/NCBI
36.	Neumann J, Bahr F, Horst D, et al: SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer. BMC Cancer. 11:5182011. View Article : Google Scholar : PubMed/NCBI
37.	Jia X, Li X, Xu Y, et al: SOX2 promotes tumorigenesis and increases the anti-apoptotic property of human prostate cancer cell. J Mol Cell Biol. 3:230–238. 2011. View Article : Google Scholar : PubMed/NCBI
38.	Yoo YM, Jung EM, Choi KC and Jeung EB: Effect of melatonin on mRNA expressions of transcription factors in murine embryonic stem cells. Brain Res. 1385:1–7. 2011. View Article : Google Scholar : PubMed/NCBI
39.	Bexell D, Gunnarsson S, Siesjö P, Bengzon J and Darabi A: CD133⁺ and nestin⁺ tumor-initiating cells dominate in N29 and N32 experimental gliomas. Int J Cancer. 125:15–22. 2009.
40.	Sobottka SB and Berger MR: Assessment of antineoplastic agents by MTT assay: partial underestimation of antiproliferative properties. Cancer Chemother Pharmacol. 30:385–393. 1992. View Article : Google Scholar : PubMed/NCBI
41.	Cajochen C, Kräuchi K and Wirz-Justice A: Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 15:432–437. 2003. View Article : Google Scholar : PubMed/NCBI
42.	Armstrong KJ and Niles LP: Induction of GDNF mRNA expression by melatonin in rat C6 glioma cells. Neuroreport. 13:473–475. 2002. View Article : Google Scholar : PubMed/NCBI
43.	Feng Z and Zhang JT: Protective effect of melatonin on beta-amyloid-induced apoptosis in rat astroglioma C6 cells and its mechanism. Free Radic Biol Med. 37:1790–1801. 2004. View Article : Google Scholar : PubMed/NCBI
44.	Liu ZG, Liu L, Xu LH, et al: Bmi-1 induces radioresistance in MCF-7 mammary carcinoma cells. Oncol Rep. 27:1116–1122. 2012.PubMed/NCBI
45.	Krupkova O Jr, Loja T, Redova M, et al: Analysis of nuclear nestin localization in cell lines derived from neurogenic tumors. Tumour Biol. 32:631–639. 2011. View Article : Google Scholar : PubMed/NCBI
46.	Loja T, Chlapek P, Kuglik P, et al: Characterization of a GM7 glioblastoma cell line showing CD133 positivity and both cytoplasmic and nuclear localization of nestin. Oncol Rep. 21:119–127. 2009.PubMed/NCBI
47.	Veselska R, Kuglik P, Cejpek P, et al: Nestin expression in the cell lines derived from glioblastoma multiforme. BMC Cancer. 6:322006. View Article : Google Scholar : PubMed/NCBI
48.	Thomas SK, Messam CA, Spengler BA, Biedler JL and Ross RA: Nestin is a potential mediator of malignancy in human neuroblastoma cells. J Biol Chem. 279:27994–27999. 2004. View Article : Google Scholar : PubMed/NCBI