Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells.
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.
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.
Yunkyung
Y
Hong
Jinyoung
J
Won
Youngjeon
Y
Lee
Seunghoon
S
Lee
Kanghui
K
Park
Kyu-Tae
KT
Chang
Yonggeun
Y
Hong
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016193:G1 Phase; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats
D008550:Melatonin
apoptosis; autophagy; cardiotoxicity; melatonin; senescence