Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells
Yunkyung Hong
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Search for more papers by this authorJinyoung Won
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Search for more papers by this authorYoungjeon Lee
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
Search for more papers by this authorSeunghoon Lee
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Search for more papers by this authorKanghui Park
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Division of Rehabilitation Medicine, Dongwei Medical Center, Busan, Korea
Search for more papers by this authorKyu-Tae Chang
National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
Search for more papers by this authorCorresponding Author
Yonggeun Hong
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Department of Physical Therapy, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Address reprint requests to Yonggeun Hong, Department of Rehabilitation Science, Graduate School of Inje University, 197 Inje-ro, Gimhae, Gyeong-nam 621-749, Korea.
E-mail: [email protected]
Kyu-Tae Chang, National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro 30, Ochang, Chung-buk 363-883, Korea.
Search for more papers by this authorYunkyung Hong
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Search for more papers by this authorJinyoung Won
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Search for more papers by this authorYoungjeon Lee
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
Search for more papers by this authorSeunghoon Lee
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Search for more papers by this authorKanghui Park
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Division of Rehabilitation Medicine, Dongwei Medical Center, Busan, Korea
Search for more papers by this authorKyu-Tae Chang
National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
Search for more papers by this authorCorresponding Author
Yonggeun Hong
Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
Department of Physical Therapy, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
Address reprint requests to Yonggeun Hong, Department of Rehabilitation Science, Graduate School of Inje University, 197 Inje-ro, Gimhae, Gyeong-nam 621-749, Korea.
E-mail: [email protected]
Kyu-Tae Chang, National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro 30, Ochang, Chung-buk 363-883, Korea.
Search for more papers by this authorAbstract
In Asia, the incidence of colorectal cancer has been increasing gradually due to a more Westernized lifestyle. The aim of study is to determine the interaction between melatonin-induced cell death and cellular senescence. We treated HCT116 human colorectal adenocarcinoma cells with 10 μm melatonin and determined the levels of cell death-related proteins and evaluated cell cycle kinetics. The plasma membrane melatonin receptor, MT1, was significantly decreased by melatonin in a time-dependent manner, whereas the nuclear receptor, RORα, was increased only after 12 hr treatment. HCT116 cells, which upregulated both pro-apoptotic Bax and anti-apoptotic Bcl-xL in the early response to melatonin treatment, activated autophagic as well as apoptotic machinery within 18 hr. Melatonin decreased the S-phase population of the cells to 57% of the control at 48 hr, which was concomitant with a reduction in BrdU-positive cells in the melatonin-treated cell population. We found not only marked attenuation of E- and A-type cyclins, but also increased expression of p16 and p-p21. Compared to the cardiotoxicity of Trichostatin A in vitro, single or cumulative melatonin treatment induced insignificant detrimental effects on neonatal cardiomyocytes. We found that 10 μm melatonin activated cell death programs early and induced G1-phase arrest at the advanced phase. Therefore, we suggest that melatonin is a potential chemotherapeutic agent for treatment of colon cancer, the effects of which are mediated by regulation of both cell death and senescence in cancerous cells with minimized cardiotoxicity.
References
- 1Edwards BK Brown ML Wingo PA et al. Annual report to the nation on the status of cancer, 1975–2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 2005; 97: 1407–1427.
- 2Byeon JS, Yang SK, Kim TI et al. Colorectal neoplasm in asymptomatic Asians: a prospective multinational multicenter colonoscopy survey. Gastrointest Endosc 2007; 65: 1015–1022.
- 3Won YJ, Sung J, Jung KW et al. Nationwide cancer incidence in Korea, 2003–2005. Cancer Res Treat 2009; 41: 122–131.
- 4Mariotto AB, Yabroff KR, Feuer EJ et al. Projecting the number of patients with colorectal carcinoma by phases of care in the US: 2000-2020. Cancer Causes Control 2006; 17: 1215–1226.
- 5Kuninaka S, Ichinose Y, Koja K et al. Suppression of manganese superoxide dismutase augments sensitivity to radiation, hyperthermia and doxorubicin in colon cancer cell lines by inducing apoptosis. Br J Cancer 2000; 83: 928–934.
- 6Tan ML, Ooi JP, Ismail N et al. Programmed cell death pathways and current antitumor targets. Pharm Res 2009; 26: 1547–1560.
- 7Yang SY, Sales KM, Fuller B et al. Apoptosis and colorectal cancer: implications for therapy. Trends Mol Med 2009; 15: 225–233.
- 8Meijer AJ, Codogno P. Autophagy: regulation and role in disease. Crit Rev Clin Lab Sci 2009; 46: 210–240.
- 9Sato K, Tsuchihara K, Fujii S et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res 2007; 67: 9677–9684.
- 10Rigas A, Dervenis C, Giannakou N et al. Selective induction of colon cancer cell apoptosis by 5-fluorouracil in humans. Cancer Invest 2002; 20: 657–665.
- 11Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370: 143–152.
- 12Kosmas C, Kallistratos MS, Kopterides P et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2008; 134: 75–82.
- 13Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005; 9: 11–24.
- 14Slominski RM, Reiter RJ Schlabritz-Loutsevitch N, et al. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol 2012; 351: 152–166.
- 15Mauriz JL, Collado PS, Veneroso C et al. A review of the molecular aspects of melatonin's anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 2013; 54: 1–14.
- 16Calvo JR, Gonzalez-Yanes C Maldonado MD. The role of melatonin in the cells of the innate immunity: a review. J Pineal Res 2013; 55: 103–120.
- 17Martín-Renedo J, Mauriz JL, Jorquera F et al. Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res 2008; 45: 532–540.
- 18Korkmaz A, Sanchez-Barcelo EJ, Tan DX et al. Role of melatonin in the epigenetic regulation of breast cancer. Breast Cancer Res Treat 2009; 115: 13–27.
- 19Bejarano I, Redondo PC, Espino J et al. Melatonin induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells. J Pineal Res 2009; 46: 392–400.
- 20Leon-Blanco MM, Guerrero JM, Reiter RJ et al. Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. J Pineal Res 2003; 35: 204–211.
- 21Kos-Kudla B, Ostrowska Z, Kozlowski A et al. Circadian rhythm of melatonin in patients with colorectal carcinoma. Neuro Endocrinol Lett 2002; 23: 239–242.
- 22Karasek M, Kowalski AJ, Suzin J et al. Serum melatonin circadian profiles in women suffering from cervical cancer. J Pineal Res 2005; 39: 73–76.
- 23Blask DE, Hill SM, Dauchy RT et al. Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. J Pineal Res 2011; 51: 259–269.
- 24Schernhammer ES, Laden F, Speizer FE et al. Night-shift work and risk of colorectal cancer in the nurses' health study. J Natl Cancer Inst 2003; 95: 825–828.
- 25Vicencio JM, Galluzzi L, Tajeddine N et al. Senescence, apoptosis or autophagy? When a damaged cell must decide its path –a mini-review. Gerontology 2008; 54: 92–99.
- 26Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92: 9363–9367.
- 27Neganova I, Lako M. G1 to S phase cell cycle transition in somatic and embryonic stem cells. J Anat 2008; 213: 30–44.
- 28Rocco JW, Sidransky D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res 2001; 264: 42–55.
- 29Bertagnolli MM, Warren RS, Niedzwiecki D, et al. p27Kip1 in stage III colon cancer: implications for outcome following adjuvant chemotherapy in cancer and leukemia group B protocol 89803. Clin Cancer Res 2009; 15: 2116–2122.
- 30Nardella C, Clohessy JG, Alimonti A et al. Pro-senescence therapy for cancer treatment. Nat Rev Cancer 2011; 11: 503–511.
- 31Kishimoto H, Aki R, Urata Y et al. Tumor-selective, adenoviral-mediated GFP genetic labeling of human cancer in the live mouse reports future recurrence after resection. Cell Cycle 2011; 10: 2737–2741.
- 32Zhuang P, Zhang Y, Cui G et al. Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B. PLoS ONE 2012; 7: e35636.
- 33Toyota N, Takano-Ohmuro H, Yoshida LS et al. Suppression of cardiac troponin T induces reduction of contractility and structural disorganization in chicken cardiomyocytes. Cell Struct Funct 2008; 33: 193–201.
- 34Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct 2002; 27: 421–429.
- 35Gewirtz DA. Autophagy, senescence and tumor dormancy in cancer therapy. Autophagy 2009; 5: 1232–1234.
- 36Sørensen NM, Schrohl AS, Jensen V et al. Comparative studies of tissue inhibitor of metalloproteinases-1 in plasma, serum and tumour tissue extracts from patients with primary colorectal cancer. Scand J Gastroenterol 2008; 43: 186–191.
- 37Schwartz RN. Management of early and advanced colorectal cancer: therapeutic issues. Am J Health Syst Pharm 2008; 65: S8–S14.
- 38Half E, Arber N. Colon cancer: preventive agents and the present status of chemoprevention. Expert Opin Pharmacother 2009; 10: 211–219.
- 39Gayet J, Zhou XP, Duval A et al. Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines. Oncogene 2001; 20: 5025–5032.
- 40Kaeser MD, Pebernard S, Iggo RD. Regulation of p53 stability and function in HCT116 colon cancer cells. J Biol Chem 2004; 279: 7598–7605.
- 41Xavier CP, Lima CF, Rohde M et al. Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation. Cancer Chemother Pharmacol 2011; 68: 1449–1457.
- 42García-Santos G, Antolín I, Herrera F et al. Melatonin induces apoptosis in human neuroblastoma cancer cells. J Pineal Res 2006; 41: 130–135.
- 43Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res 2009; 47: 8–14.
- 44Zhang S, Qi Y, Zhang H et al. Melatonin inhibits cell growth and migration, but promotes apoptosis in gastric cancer cell line, SGC7901. Biotech Histochem 2013; 88: 281–289.
- 45Wang J, Xiao X, Zhang Y et al. Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res 2012; 53: 77–90.
- 46Uguz AC, Cig B, Espino J et al. Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells. J Pineal Res 2012; 53: 91–98.
- 47Min KJ, Kim HS, Park EJ et al. Melatonin enhances thapsigargin-induced apoptosis through reactive oxygen species-mediated upregulation of CCAAT-enhancer-binding protein homologous protein in human renal cancer cells. J Pineal Res 2012; 53: 99–106.
- 48Shin DY, Lee WS, Lu JN et al. Induction of apoptosis in human colon cancer HCT-116 cells by anthocyanins through suppression of Akt and activation of p38-MAPK. Int J Oncol 2009; 35: 1499–1504.
- 49Johnson SM, Gulhati P, Arrieta I et al. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res 2009; 29: 3185–3190.
- 50Ciechomska IA, Goemans GC, Skepper JN, et al. Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function. Oncogene 2009; 28: 2128–2141.
- 51Tanida I, Minematsu-Ikeguchi N, Ueno T et al. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 2005; 1: 84–91.
- 52Young AR, Narita M, Ferreira M et al. Autophagy mediates the mitotic senescence transition. Genes Dev 2009; 23: 798–803.
- 53Sasaki M, Miyakoshi M, Sato Y et al. Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis. Lab Invest 2010; 90: 835–843.
- 54Wajapeyee N, Serra RW, Zhu X et al. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 2008; 132: 363–374.
- 55Mallette FA, Gaumont-Leclerc MF, Ferbeyre G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 2007; 21: 43–48.
- 56Narita M, Narita M, Krizhanovsky V et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 2006; 126: 503–514.
- 57Lleonart ME, Artero-Castro A, Kondoh H. Senescence induction; a possible cancer therapy. Mol Cancer 2009; 8: 3.
- 58Sliwinska MA, Mosieniak G, Wolanin K et al. Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells. Mech Ageing Dev 2009; 130: 24–32.
- 59Fujiwara K, Daido S, Yamamoto A et al. Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy. J Biol Chem 2008; 283: 388–397.
- 60Pizarro JG, Yeste-Velasco M, Esparza JL et al. The antiproliferative activity of melatonin in B65 rat dopaminergic neuroblastoma cells is related to the downregulation of cell cycle-related genes. J Pineal Res 2008; 45: 8–16.
- 61Cabrera J, Negrín G, Estévez F et al. Melatonin decreases cell proliferation and induces melanogenesis in human melanoma SK-MEL-1 cells. J Pineal Res 2010; 49: 45–54.
- 62Pandi-Perumal SR, Trakht I, Srinivasan V et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 2008; 85: 335–353.
- 63Jetten AM. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 2009; 7: 1–32.
10.1621/nrs.07003 Google Scholar
- 64Poon AM, Mak AS, Luk HT et al. Melatonin and [125]iodomelatonin binding sites in the human colon. Endocr Res 1996; 22: 77–94.
- 65Nemeth C, Humpeler S, Kallay E et al. Decreased expression of the melatonin receptor 1 in human colorectal adenocarcinomas. J Biol Regul Homeost Agents 2011; 25: 531–542.
- 66Winczyk K, Pawlikowski M, Guerrero JM et al. Possible involvement of the nuclear RZR/ROR-alpha receptor in the antitumor action of melatonin on murine Colon 38 cancer. Tumour Biol 2002; 23: 298–302.
- 67Yeh ET, Tong AT, Lenihan DJ et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 2004; 109: 3122–3131.
- 68Karagiannis TC, Lin AJ, Ververis K et al. Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes. Aging (Albany NY) 2010; 2: 659–668
- 69Platta CS, Greenblatt DY, Kunnimalaiyaan M et al. The HDAC inhibitor trichostatin A inhibits growth of small cell lung cancer cells. J Surg Res 2007; 142: 219–226
- 70Wu ZQ, Zhang R, Chao C et al. Histone deacetylase inhibitor trichostatin A induced caspase-independent apoptosis in human gastric cancer cell. Chin Med J (Engl) 2007; 120: 2112–2118.
- 71Habold C, Poehlmann A, Bajbouj K et al. Trichostatin A causes p53 to switch oxidative-damaged colorectal cancer cells from cell cycle arrest into apoptosis. J Cell Mol Med 2008; 12: 607–621.
- 72Zhang F, Zhang T, Teng ZH et al. Sensitization to gamma-irradiation-induced cell cycle arrest and apoptosis by the histone deacetylase inhibitor trichostatin A in non-small cell lung cancer (NSCLC) cells. Cancer Biol Ther 2009; 8: 823–831.
- 73Herold C, Ganslmayer M, Ocker M et al. The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells. J Hepatol 2002; 36: 233–240.
- 74Renthal W, Nestler EJ. Histone acetylation in drug addiction. Semin Cell Dev Biol 2009; 20: 387–394.
- 75Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 2008; 269: 7–17.
- 76Reiter RJ, Tan DX, Sainz RM et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 2002; 54: 1299–1321.
- 77Vigushin DM, Ali S, Pace PE et al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 2001; 7: 971–976.
- 78Elaut G, Laus G, Alexandre E et al. A metabolic screening study of trichostatin A (TSA) and TSA-like histone deacetylase inhibitors in rat and human primary hepatocyte cultures. J Pharmacol Exp Ther 2007; 321: 400–408.
- 79Sainz RM, Mayo JC, Rodriguez C et al. Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 2003; 60: 1407–1426.
