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

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.

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…For example, melatonin upregulates Bax and the conversion of caspase-3 to cleaved form in human colorectal cancer cells [15]. Melatonin also promotes Bcl-2 down-regulation [10], suggesting that it may be an important endogenous cell death modulator.…”

“…Antiproliferative effects delaying the entrance of cells into the S phase) or by arresting cells in the G2/M phase [15]. Prolonging G1 and delaying progression to S phase is one way that melatonin drives tumor cells to become more differentiated.…”

Melatonin action in tumor skeletal muscle cells: an ultrastructural study

“…Since then, this pineal neurohormone Mel has been repeatedly described as a potential anti-cancer molecular tool given its demonstrated pro-apoptotic effect and oncostatic action towards different cancer cell lines (Bizzarri et al, 2013;Perdomo et al, 2013;Rodriguez et al, 2013;Hong et al, 2014), therefore contributing to cancer protection (Hrushesky et al, 2009;Mao et al, 2010;Bukowska, 2011;Santoro et al, 2012).…”

“…Additionally, Kubatka et al (2001) demonstrated the anti-tumor action of Mel in breast cancer in vivo, and this effect was then confirmed in clinical studies showing its protective effect from mammary carcinogenesis (Nowfar et al, 2002) and in other neoplastic diseases (Hong et al, 2014;Wu et al, 2015).…”

Oral Mucositis: Melatonin Gel an Effective New Treatment

“…Melatonin gel treatment in the mouth, which was observed to reduce intestinal morpho-pathological changes [17], is therefore also associated with improved preservation of both small intestinal and oral mucosa. including breast, endometrial, prostate, colon and ovarian cancers as well as choriocarcinoma, melanoma, neuroblastoma and osteosarcoma among others [109][110]. Its oncostatic mechanisms are associated with several hallmarks of cancer.…”