The protective role of melatonin in cadmium-induced proliferation of ovarian cancer cells
Abstract
Cadmium (Cd), a ubiquitous environmental and occupational pollutant, acts as a metalloestrogen to induce cell proliferation. It is suggested that Cd may also contribute to the development of estrogen-related cancers like ovarian cancer which is the most lethal cancer in women. Furthermore, it was shown that melatonin has antiproliferative effect on estradiol (E2)-induced proliferation. The aim of the present study was to evaluate whether melatonin inhibits Cd-induced proliferation in ovarian cancer cell lines and also whether Cd and melatonin can modulate estrogen receptor α (ERα) expression. OVCAR3 and SKOV3 human ovarian cancer cell lines were treated with CdCl2 (1-100 nM) and melatonin (1 µM) for 48 h. Cell proliferation evaluation was carried out by bromodeoxyuridine (BrdU) incorporation assay. ERα expression was detected by western blotting method 24 h after cell treatment. The results were demonstrated that Cd increased proliferation of ovarian cancer cell lines in a dose dependent manner. Melatonin inhibited Cd-induced proliferation of OVCAR3 and SKOV3 cell lines. Moreover, CdCl2 significantly increased ERα expression in both OVCAR3 and SKOV3 cell lines compared to control. Melatonin significantly inhibited Cd inducing effect on ERα expression of OVCAR3 and SKOV3 cell. In conclusion, due to the proliferative effect on ovarian cancer cell lines, Cd could play an important role in the etiology of ovarian cancer by inducing cells ERα expression. Furthermore, melatonin has the protective role on Cd-induced cell proliferation by inhibition of ERα expression.
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Satarug S, Moore MR. Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect. 2004; 112(10):1099–1103.
Järup L. Hazards of heavy metal contamination. Br Med Bull. 2003;68(1):167–182.
Garcia-Morales P, Saceda M, Kenney N, Kim N, Salomon DS, Gottardis MM, et al. Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem. 1994;269(24):16896–16901.
Darbre PD. Metalloestrogens: an emerging class of inorganic xenoestrogens with potential to add to the oestrogenic burden of the human breast. J Appl Toxicol. 2006;26(3):191–197.
Safe S. Cadmium’s disguise dupes the estrogen receptor. Nat Med. 2003;9:1000–1001.
Hajiahmadi S, Panjehpour M, Aghaei M, Mousavi S. Molecular expression of adenosine receptors in OVCAR-3, Caov-4 and SKOV-3 human ovarian cancer cell lines. Res Pharm Sci. 2015;10(1):43–51.
Dong X, Men X, Zhang W, Lei P. Advances in tumor markers of ovarian cancer for early diagnosis. Indian J Cancer. 2014;51(3):72-76.
Adams SV, Quraishi SM, Shafer MM, Passarelli MN, Freney EP, Chlebowski RT, et al. Dietary cadmium exposure and risk of breast, endometrial, and ovarian cancer in the Women’s Health Initiative. Environ Health Perspect. 2014;122(6):594–600.
Adams SV, Passarelli MN, Newcomb PA. Cadmium exposure and cancer mortality in the third national health and nutrition examination survey cohort. Occup Environ Med. 2012;69(2):153-156.
Chuffa LG de A, Reiter RJ, Lupi Júnior LA. Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms. Carcinogenesis. 2017;38(10):945-952
Martínez-Campa C, Alonso-González C, Mediavilla MD, Cos S, González A, Ramos S, et al. Melatonin inhibits both ER alpha activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium. J Pineal Res. 2006;40(4):291–296.
Shen CJ, Chang CC, Chen YT, Lai CS, Hsu YC. Melatonin suppresses the growth of ovarian cancer cell lines (OVCAR-429 and PA-1) and potentiates the effect of G1 arrest by targeting CDKS. Int J Mol Sci. 2016;17(2): pii: E176. doi: 10.3390/ijms17020176.
Futagami M, Sato S, Sakamoto T, Yokoyama Y, Saito Y. Effects of melatonin on the proliferation and cis-diamminedichloroplatinum (CDDP) sensitivity of cultured human ovarian cancer cells. Gynecol Oncol. 2001;82(3):544–549.
Cos S, Fernández R, Güézmes A, Sánchez-Barceló EJ. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998;58(19):4383–4390.
del Río B, García Pedrero JM, Martínez-Campa C, Zuazua P, Lazo PS, Ramos S. Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem. 2004;279(37):38294–38302.
Siewit CL, Gengler B, Vegas E, Puckett R, Louie MC. Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun. Mol Endocrinol. 2010;24(5):981–992.
Bukowska A. Anticarcinogenic role of melatonin-potential mechanisms. Med Pr. 2011;62(4):425–434.
Ma Z, Yang Y, Fan C, Han J, Wang D, Di S, et al. Melatonin as a potential anticarcinogen for non-small-cell lung cancer. Oncotarget. 2016;7(29):46768-46784.
Yeh CM, Su SC, Lin CW, Yang WE, Chien MH, Reiter RJ, et al. Melatonin as a potential inhibitory agent in head and neck cancer. Oncotarget. 2017;8(52):90545–90556.
Mehta A, Kaur G. Potential role of melatonin in prevention and treatment of oral carcinoma. Indian J Dent. 2014;5(2):86-91.
Alonso-González C, González A, Mazarrasa O, Güezmes A, Sánchez-Mateos S, Martínez-Campa C, et al. Melatonin prevents the estrogenic effects of sub-chronic administration of cadmium on mice mammary glands and uterus. J Pineal Res. 2007;42(4):403–410.
Eriksen KT, Halkjær J, Sørensen M, Meliker JR, McElroy JA, Tjønneland A, et al. Dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal women: a prospective cohort study. PloS One. 2014;9(6): 1008-1015.
Julin B, Wolk A, Åkesson A. Dietary cadmium exposure and risk of epithelial ovarian cancer in a prospective cohort of Swedish women. Br J Cancer. 2011;105(3):441–444.
Brama M, Gnessi L, Basciani S, Cerulli N, Politi L, Spera G, et al. Cadmium induces mitogenic signaling in breast cancer cell by an ERα-dependent mechanism. Mol Cell Endocrinol. 2007;264 (1–2):102–108.
Zhang W, Yang J, Wang J, Xia P, Xu Y, Jia H, et al. Comparative studies on the increase of uterine weight and related mechanisms of cadmium and p-nonylphenol. Toxicology. 2007;241(1–2):84–91.
Gao X, Yu L, Moore AB, Kissling GE, Waalkes MP, Dixon D. Cadmium and proliferation in human uterine leiomyoma cells: evidence of a role for EGFR/MAPK pathways but not classical estrogen receptor pathways. Environ Health Perspect. 2015; 123(4):331–336.
Jiang G, Duan W, Xu L, Song S, Zhu C, Wu L. Biphasic effect of cadmium on cell proliferation in human embryo lung fibroblast cells and its molecular mechanism. Toxicol In Vitro. 2009; 23(6):973–978.
Hao C, Hao W, Wei X, Xing L, Jiang J, Shang L. The role of MAPK in the biphasic dose-response phenomenon induced by cadmium and mercury in HEK293 cells. Toxicol In Vitro.. 2009;23(4): 660–666.
Huff MO, Todd SL, Smith AL, Elpers JT, Smith AP, Murphy RD, et al. Arsenite and cadmium activate mapk/erk via membrane estrogen receptors and g-protein coupled estrogen receptor signaling in human lung adenocarcinoma cells. Toxicol Sci. 2016;152(1):62–71.
Khojastehfar A, Aghaei M, Gharagozloo M, Panjehpour M. Cadmium induces reactive oxygen species-dependent apoptosis in MCF-7 human breast cancer cell line. Toxicol Mech Methods. 2015;25(1):48–55.
Martínez-Campa CM, Alonso-González C, Mediavilla MD, Cos S, González A, Sanchez-Barcelo EJ. Melatonin down-regulates hTERT expression induced by either natural estrogens (17β-estradiol) or metalloestrogens (cadmium) in MCF-7 human breast cancer cells. Cancer Lett. 2008;268(2):272–277.
Alonso-Gonzalez C, Mediavilla D, Martinez-Campa C, Gonzalez A, Cos S, Sanchez-Barcelo EJ. Melatonin modulates the cadmium-induced expression of MT-2 and MT-1 metallothioneins in three lines of human tumor cells (MCF-7, MDA-MB-231 and HeLa). Toxicol Lett. 2008;181(3): 190–195.
Sánchez-Barceló EJ, Cos S, Mediavilla D, Martínez-Campa C, González A, Alonso-González C. Melatonin-estrogen interactions in breast cancer. J Pineal Res. 2005 May;38(4):217–222.
Sieh W, Köbel M, Longacre TA, Bowtell DD, deFazio A, Goodman MT, et al. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol. 2013;14(9):853–862.
Oncol. 2013;14(9):853–862.
Wei Z, Song X, Shaikh ZA. Cadmium promotes the proliferation of triple-negative breast cancer cells through EGFR-mediated cell cycle regulation. Toxicol Appl Pharmacol. 2015;289(1):98–108.
Ronchetti SA, Miler EA, Duvilanski BH, Cabilla JP. Cadmium mimics estrogen-driven cell proliferation and prolactin secretion from anterior pituitary cells. PLoS One. 2013;8(11): e81101.
Liu L, Li D, Gilbert ER, Xiao Q, Zhao X, Wang Y, et al. Effect of monochromatic light on expression of estrogen receptor (ER) and progesterone receptor (PR) in ovarian follicles of chicken. PloS One. 2015;10(12):0144102.
Hill SM, Collins A, Kiefer TL. The modulation of oestrogen receptor-alpha activity by melatonin in MCF-7 human breast cancer cells. Eur J Cancer. 2000;36:117–118.
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