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Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells

Authors

  • Yunkyung Hong,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
    3. Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
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  • Jinyoung Won,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
    3. Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
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  • Youngjeon Lee,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
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  • Seunghoon Lee,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
    3. Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
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  • Kanghui Park,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Division of Rehabilitation Medicine, Dongwei Medical Center, Busan, Korea
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  • Kyu-Tae Chang,

    1. National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
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  • Yonggeun Hong

    Corresponding author
    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
    3. Ubiquitous Healthcare Research Center, Inje University, Gimhae, Korea
    4. 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: yonghong@inje.ac.kr

      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.

      E-mail: changkt@kribb.re.kr

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Abstract

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.

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