Issue
Effects of melatonin on apoptosis and cell differentiation in MCF-7 derived cancer stem cells
Corresponding Author(s) : Nadir Koçak
Cellular and Molecular Biology,
Vol. 64 No. 12: Issue 12
Abstract
Melatonin is a hormone of the pineal gland that has a wide range of biological effects such as antioxidant, anti-inflammatory, and anti-tumor activity. Previous studies have shown that melatonin also affects survival, proliferation, and apoptosis of the cells. In this study, we investigated the effect of melatonin on apoptosis, self-renewal, and differentiation. For this purpose, MCF-7 and HEK293 cells were subjected to melatonin treatment. Expression of genes related to apoptosis (Bax and Bcl2) and self-renewal and differentiation (Oct4, Sox2, and Nanog) analyzed after the sorting of cancer stem cells from MCF-7 cells. Results showed that the effect of melatonin is dependent on the melatonin concentration and treatment periods. Melatonin treatment decreased the cell proliferation rate of MCF-7 in contrast to HEK293. Also, this treatment increased apoptosis in MCF-7 cells and decreased in HEK293 cells. Gene expression of Nanog was decreased and Sox2 was increased in both cell groups after the melatonin treatment. Expression of Oct4 was decreased in MCF-7 cells and increased in HEK293 cells. We determined that melatonin decreases apoptosis and differentiation of stem cells in normal HEK293 stem cells, but increases apoptosis and differentiation in the MCF-7 cancer stem cells.
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- World Cancer Report, 2014
- Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, Naghavi M. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis, Lancet, 2011; 378: 1461-1484.
- Wicha MS, Liu S, Dontu G, Cancer stem cells: an old idea-a paradigm shift,Cancer Res. 2006; 66(4): 1883–1890.
- Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acutemyeloid leukemia after transplantation into SCID mice, Nature 1994; 367: 645–648.
- Bonnet D, Dick JE. Human acute myeloid leukemia is organized as ahierarchy that originates from a primitive hematopoietic cell, Nat. Med. 1997; 3(7): 730–737.
- Hermann PC, Bhaskar S, Cioffi M, Heeschen C. Cancer stem cells in solidtumors, Semin. Cancer Biol. 2010; 20(2): 77–84.
- Visvader JE, Lindeman GJ. Cancer stem cells in solid tumors: accumulatingevidence and unresolved questions, Nat. Rev. Cancer 2008; 8(10): 755–768.
- Clevers H. The cancer stem cell: premises, promises, and challenges, Nat.Med. 2011: 17(3): 313–319.
- Sampieri K, Fodde R. Cancer stem cells and metastasis, Semin. Cancer Biol. 2012; 22(3): 187–193.
- Jemal A, Siegel R., Xu J, Ward E. Cancer statistics, 2010. CA Cancer J. Clin. 2010; 60: 277–300.
- Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 2003; 101: 3142–3149.
- Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor SB, Crawford J, Cross SJ. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J. Clin. Oncol. 2006; 2: 3187–3205.
- Morrison R, Schleicher SM, Sun Y, Niermann KJ, Kim S, Spratt DE, et al. Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. J Oncol 2011; 2011: 941876.
- Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 2009; 8: 806-823.
- Prud´homme GJ. Cancer stem cells and novel targets for antitumor strategies. Curr Pharm Des 2012; 18: 2838-2849.
- Winquist RJ, Boucher DM, Wood M, Furey BF. Targeting cancer stem cells for more effective therapies: taking out cancer´s locomotive engine. BiochemPharmacol 2009; 78: 326-334.
- Kawasaki BT, Hurt EM, Mistree T, Farrar WL. Targeting cancer stem cells with phytochemicals.MolInterv 2008; 8: 174-184.
- Naujokat C, Fuchs D, Opelz G. Salinomycin in cancer: a new mission for an old agent. Mol Med Report 2010; 3: 555-559.
- Naujokat C, Laufer S. 2012. Salinomycin, a candidate drug for the elimination of cancer stem cells. In: Dittmar T, Mihich E, Zänker KS, editors. Role of cancer stem cells in cancer biology and therapy. 1st ed. New Hampshire: Science Publishers 2013: in press.
- Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J NutrBiochem 2011; 22: 799-806.
- Burnett J, Newman B, Sun D. Targeting cancer stem cells with natural products. Curr Drug Targets 2012; 13: 1054-1064.
- Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan JL, Dontu G, Wicha MS. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 2010; 120: 485-497.
- Hirsch HA, Illiopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together withchemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69: 7507-7511.
- Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin- Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 2011; 126: 355-64.
- Del Barco SD, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Catillo B, Menedez JA. Metformin: multi-faceted protection against cancer. Oncotarget 2012; 2: 896-917.
- Rattan R, Ali Fehmi R, Munkarah A. Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. J Oncol 2012; 2012: 928127.
- Prud´homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S. Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PloS One 2010; 5: e13831.
- Sachlos E, Risueno RM, Laroonde S, Shapovalova Z, Lee JH, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, Levadoux-Martin M, Lee JB, Giacomelli AO, Hassell JA, Fischer-Russell D, Trus MR, Foley R, Leber B, Xenocostas A, Brown ED, Collins TJ, Bhatia M. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 2012; 149: 1284-97.
- Macchi, MM, Bruce, JN. Human pineal physiology and functional significance of melatonin. Front. Neuroendocrinol. 2004; 25: 177–195.
- Skwarlo-Sonta, K. Melatonin in immunity: Comparative aspects. NeuroEndocrinol.Lett. 2002; 2: 61–66.
- Blask DE, Hill SM., Effects of melatonin on cancer: studies on MCF-7 human breast cancer cells in culture, J Neural Transm Suppl. 1986; 21: 433-449.
- Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro, Life Sci. 1999; 65: 415-420.
- Hastings M, Reddy AB, Maywood ES. A clockwork web: circadian timing in brain and periphery, in health and disease. Nature Reviews Neuroscience. 2003; 4: 649–661.
- Eck KM, Yuan L, Duffy L, Ram PT, Ayettey S, Chen I, Cohn CS, Reed JC, Hill SM. A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumor cells. British Journal of Cancer. 1998; 77: 2129–2137.
- Teplitzky SR, Kiefer TL, Cheng Q, Dwivedi PD, Moroz K, Myers L, Anderson MB, Collins A, Dai J, Yuan L, Springgs LL, Blask DE, Hill SM. Chemoprevention of NMU-induced rat mammary carcinoma with the combination of melatonin and 9-cis-retinoic acid. Cancer Letters. 2001;168:155–163.
- Melancon K, Cheng Q, Kiefer TL, Dai J, Lai L, Dong C, Yuan L, Collins A, Thiyagarajah A, Long S, Hill SM. Regression of NMU-induced mammary tumors with the combination of melatonin and 9-cis-retinoic acid. Cancer Letters. 2005;227:39–48.
- Proietti S, Cucina A, D'Anselmi F, Dinicola S, Pasqualato A, Lisi E, Bizzarri M. Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. Journal of Pineal Research. 2011;50:150–158.
- Adb El-Aziz MA, Hassan HA, Mohamed MH, Meki AR, Abdel-Ghaffar SK, Hussein MR. The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigellsatvia in mammary carcinoma: an animal model. International.Journal of Experimental Pathology. 2005;86:383–396.
- Cucina A, Proietti S, D'Anselmi F, Coluccia P, Dinicola S, Frati L, Bizzarri M. Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. Journal of Pineal Research. 2009;46:172–180.
- Martinez CM., Oxygen free radicals and human disease, Biochimie., 77, 147-161, (1995).
- Cos S, Blask DE, Lemus-Wilson A, Hill AB. Effects of melatonin on the cell cycle kinetics and "estrogen-rescue” of MCF-7 human breast cancer cells in culture. Journal of Pineal Research.1991; 10:36–42.
- Bizzarri M, Cucina A, Valente MG, Tagliaferri F, Borrelli V, Stipa F, Cavallaro A. Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures, J Surg Res.2003: 110: 332–337.
- Sandyk R. Is the pineal gland involved in the pathogenesis of endometrial carcinoma? Int J Neurosci. 1992; 62: 89-96.
- Wenzel U, Nickel A, Daniel H. Melatonin potentiates flavone-induced apoptosis in human colon cancer cells by increasing the level of glycolytic end products. Int J Cancer. 2005; 116: 236–242.
- Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2, Nat. Biotechnol. 2008; 26: 1269–1275.
- Rho S., Kim BR, Kang S, A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3"²-kinase (PI3K)/AKT pathway in ovarian cancer cells, GynecolOncol. 2011; 120: 121–127.
References
World Cancer Report, 2014
Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, Naghavi M. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis, Lancet, 2011; 378: 1461-1484.
Wicha MS, Liu S, Dontu G, Cancer stem cells: an old idea-a paradigm shift,Cancer Res. 2006; 66(4): 1883–1890.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acutemyeloid leukemia after transplantation into SCID mice, Nature 1994; 367: 645–648.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as ahierarchy that originates from a primitive hematopoietic cell, Nat. Med. 1997; 3(7): 730–737.
Hermann PC, Bhaskar S, Cioffi M, Heeschen C. Cancer stem cells in solidtumors, Semin. Cancer Biol. 2010; 20(2): 77–84.
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumors: accumulatingevidence and unresolved questions, Nat. Rev. Cancer 2008; 8(10): 755–768.
Clevers H. The cancer stem cell: premises, promises, and challenges, Nat.Med. 2011: 17(3): 313–319.
Sampieri K, Fodde R. Cancer stem cells and metastasis, Semin. Cancer Biol. 2012; 22(3): 187–193.
Jemal A, Siegel R., Xu J, Ward E. Cancer statistics, 2010. CA Cancer J. Clin. 2010; 60: 277–300.
Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 2003; 101: 3142–3149.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor SB, Crawford J, Cross SJ. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J. Clin. Oncol. 2006; 2: 3187–3205.
Morrison R, Schleicher SM, Sun Y, Niermann KJ, Kim S, Spratt DE, et al. Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. J Oncol 2011; 2011: 941876.
Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 2009; 8: 806-823.
Prud´homme GJ. Cancer stem cells and novel targets for antitumor strategies. Curr Pharm Des 2012; 18: 2838-2849.
Winquist RJ, Boucher DM, Wood M, Furey BF. Targeting cancer stem cells for more effective therapies: taking out cancer´s locomotive engine. BiochemPharmacol 2009; 78: 326-334.
Kawasaki BT, Hurt EM, Mistree T, Farrar WL. Targeting cancer stem cells with phytochemicals.MolInterv 2008; 8: 174-184.
Naujokat C, Fuchs D, Opelz G. Salinomycin in cancer: a new mission for an old agent. Mol Med Report 2010; 3: 555-559.
Naujokat C, Laufer S. 2012. Salinomycin, a candidate drug for the elimination of cancer stem cells. In: Dittmar T, Mihich E, Zänker KS, editors. Role of cancer stem cells in cancer biology and therapy. 1st ed. New Hampshire: Science Publishers 2013: in press.
Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J NutrBiochem 2011; 22: 799-806.
Burnett J, Newman B, Sun D. Targeting cancer stem cells with natural products. Curr Drug Targets 2012; 13: 1054-1064.
Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan JL, Dontu G, Wicha MS. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 2010; 120: 485-497.
Hirsch HA, Illiopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together withchemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69: 7507-7511.
Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin- Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 2011; 126: 355-64.
Del Barco SD, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Catillo B, Menedez JA. Metformin: multi-faceted protection against cancer. Oncotarget 2012; 2: 896-917.
Rattan R, Ali Fehmi R, Munkarah A. Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. J Oncol 2012; 2012: 928127.
Prud´homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S. Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PloS One 2010; 5: e13831.
Sachlos E, Risueno RM, Laroonde S, Shapovalova Z, Lee JH, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, Levadoux-Martin M, Lee JB, Giacomelli AO, Hassell JA, Fischer-Russell D, Trus MR, Foley R, Leber B, Xenocostas A, Brown ED, Collins TJ, Bhatia M. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 2012; 149: 1284-97.
Macchi, MM, Bruce, JN. Human pineal physiology and functional significance of melatonin. Front. Neuroendocrinol. 2004; 25: 177–195.
Skwarlo-Sonta, K. Melatonin in immunity: Comparative aspects. NeuroEndocrinol.Lett. 2002; 2: 61–66.
Blask DE, Hill SM., Effects of melatonin on cancer: studies on MCF-7 human breast cancer cells in culture, J Neural Transm Suppl. 1986; 21: 433-449.
Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro, Life Sci. 1999; 65: 415-420.
Hastings M, Reddy AB, Maywood ES. A clockwork web: circadian timing in brain and periphery, in health and disease. Nature Reviews Neuroscience. 2003; 4: 649–661.
Eck KM, Yuan L, Duffy L, Ram PT, Ayettey S, Chen I, Cohn CS, Reed JC, Hill SM. A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumor cells. British Journal of Cancer. 1998; 77: 2129–2137.
Teplitzky SR, Kiefer TL, Cheng Q, Dwivedi PD, Moroz K, Myers L, Anderson MB, Collins A, Dai J, Yuan L, Springgs LL, Blask DE, Hill SM. Chemoprevention of NMU-induced rat mammary carcinoma with the combination of melatonin and 9-cis-retinoic acid. Cancer Letters. 2001;168:155–163.
Melancon K, Cheng Q, Kiefer TL, Dai J, Lai L, Dong C, Yuan L, Collins A, Thiyagarajah A, Long S, Hill SM. Regression of NMU-induced mammary tumors with the combination of melatonin and 9-cis-retinoic acid. Cancer Letters. 2005;227:39–48.
Proietti S, Cucina A, D'Anselmi F, Dinicola S, Pasqualato A, Lisi E, Bizzarri M. Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. Journal of Pineal Research. 2011;50:150–158.
Adb El-Aziz MA, Hassan HA, Mohamed MH, Meki AR, Abdel-Ghaffar SK, Hussein MR. The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigellsatvia in mammary carcinoma: an animal model. International.Journal of Experimental Pathology. 2005;86:383–396.
Cucina A, Proietti S, D'Anselmi F, Coluccia P, Dinicola S, Frati L, Bizzarri M. Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. Journal of Pineal Research. 2009;46:172–180.
Martinez CM., Oxygen free radicals and human disease, Biochimie., 77, 147-161, (1995).
Cos S, Blask DE, Lemus-Wilson A, Hill AB. Effects of melatonin on the cell cycle kinetics and "estrogen-rescue” of MCF-7 human breast cancer cells in culture. Journal of Pineal Research.1991; 10:36–42.
Bizzarri M, Cucina A, Valente MG, Tagliaferri F, Borrelli V, Stipa F, Cavallaro A. Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures, J Surg Res.2003: 110: 332–337.
Sandyk R. Is the pineal gland involved in the pathogenesis of endometrial carcinoma? Int J Neurosci. 1992; 62: 89-96.
Wenzel U, Nickel A, Daniel H. Melatonin potentiates flavone-induced apoptosis in human colon cancer cells by increasing the level of glycolytic end products. Int J Cancer. 2005; 116: 236–242.
Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2, Nat. Biotechnol. 2008; 26: 1269–1275.
Rho S., Kim BR, Kang S, A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3"²-kinase (PI3K)/AKT pathway in ovarian cancer cells, GynecolOncol. 2011; 120: 121–127.