Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway

Song, Jun; Ma, Sai-Jun; Luo, Jianhua; Zhang, Hui; Wang, Ri-Xiong; Liu, Hui; Li, Li; Zhang, Zhiguang; Ruixiang, Zhou

doi:10.3892/or.2018.6282

Cited by 50 publications

(48 citation statements)

References 58 publications

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“…However, the relationship between AKT, MDM2, and membrane receptors of melatonin should be confirmed by the more experiments. The conclusion partly confirms our precious study on melatonin against SGC‐7901, another human gastric cancer cell line (Song et al, ). But, the change of p53 was inconsistent in these three cell lines, which inferred that there were other molecules involved in the downregulation of MDM2 besides of p53.…”

Section: Discussionsupporting

confidence: 86%

Downregulation of AKT and MDM2, Melatonin Induces Apoptosis in AGS and MGC803 Cells

Jun

Luo

et al. 2019

The Anatomical Record

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Melatonin, a neurohormone secreted by the pineal gland, has a variety of biological functions, such as circadian rhythms regulation, anti-oxidative activity, immunomodulatory effects, and anittumor, etc. At present, its antitumor effect has attracted people's attention due to its extensive tissue distribution, good tissue compatibility, and low toxic and side effects. In the gastrointestinal tract, there is high level of melatonin and many studies showed melatonin has effects of anti-gastric cancer. In this experiment, human gastric cancer cell lines AGS and MGC803 were used to investigate the intracellular molecular mechanism of melatonin against gastric cancer. After AGS and MGC803 have been treated with melatonin, the changes of cell morphology and cellular structure were observed under electron microscope. Flow cytometer and apoptosis detection kits were used to analyze the effect of apoptosis on AGS and MGC803. The alterations of apoptosis-related proteins Caspase 9, Caspase 3, and upstream regulators AKT, MDM2 including expression, phosphorylation, and activation were detected to analyze the intracellular molecular mechanism of melatonin inhibiting gastric cancer. In AGS and MGC803 cells with melatonin exposure, cleaved Caspase 9 was upregulated and Caspase 3 was activated; moreover, MDM2 and AKT expression and phosphorylation were downregulated. Melatonin promoted apoptosis of AGS and MGC803 cells by the downregulation of AKT and MDM2. Anat Rec, 302:1544-

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Section: Discussionsupporting

confidence: 86%

Downregulation of AKT and MDM2, Melatonin Induces Apoptosis in AGS and MGC803 Cells

Jun

Luo

et al. 2019

The Anatomical Record

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“…By not observing signs of cytotoxicity in the cells, we studied whether melatonin exerted that antiproliferative effect in vitro due to an arrest at some stage of the cell cycle, since as we have mentioned previously other groups have demonstrated the effect of melatonin as an antiproliferative molecule when blocks the cells in the G0 and G1 phases of the cell cycle [36,37]. When analyzing the cell cycle in B16-F10 cells, we observed that the groups treated with melatonin had a greater number of events in G1, as previously published by other groups, as well as in G2/M.…”

Section: Discussionmentioning

confidence: 99%

Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation

Álvarez-Artime¹,

Cernuda-Cernuda²,

Naveda³

et al. 2020

IJMS

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Neuroindole melatonin, a hormone synthesized during the night mainly—but not exclusively—by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of the most common carcinomas among developed countries and a type of tumor particularly difficult to fight back in medium/advanced stages. In contrast to other types of cancer, influence of melatonin on melanoma has been scarcely investigated. Thus, we have chosen the murine melanoma model B16-F10 cell line to study antiproliferative and antitumoral actions of melatonin. For this purpose, we combined both, cell culture and in vivo models. Melatonin reduced either, growth rate or migration of B16-F10 cells. Furthermore, melanin synthesis was altered by melatonin, promoting its synthesis. Melatonin also induced a G2/M cell cycle arrest and altered the cytoskeletal organization. To corroborate these results, we tested the effect of melatonin in the in vivo model of B16-F10 cell injection in the tail vein, which causes numerous lung metastases. Two different strategies of melatonin administration were used, namely, in drinking water, or daily intraperitoneal injection. However, contrary to what occurred in cell culture, no differences were observed between control and melatonin treated groups. Results obtained led us to conclude that melatonin exerts an antiproliferative and anti-migrating effect on this melanoma model by interfering with the cytoskeleton organization, but this pharmacological effect cannot be translated in vivo as the indole did not prevent metastasis in the murine model, suggesting that further insights into the effects of the indole in melanoma cells should be approached to understand this apparent paradox.

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“…Our previous experiments established the different concentrations of MLT which were able to intervene in a murine model of gastric cancer, and it was found that MLT reduced tumor volume and weight, achieved antitumor effects, and directly downregulated CD4 + CD25 + Treg cells and Foxp3 expression in gastric cancer tissue (14). Different concentrations of MLT have been found to inhibit the proliferation of human gastric cancer cell lines MGC-803, SGC-7901 (15) and AGS (16), and the murine gastric cancer MFC cell line (14) in a time-dose dependent manner. Selective addition of Treg cells or CD4 + CD25 -T cells to co-cultures revealed that MLT inhibited the proliferation of MFC gastric cancer cells in a dose-dependent manner (17).…”

Section: Introductionmentioning

confidence: 99%

Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo

Liu

Zhu

et al. 2019

Oncol Rep

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Transforming growth factor β (TGF-β) is a polypeptide growth factor with various biological activities, and is widely distributed in various tissues. In mammals, TGF-β has three isoforms: TGF-β1, 2, and 3, of which TGF-β1 is most abundant in the TGF-β family. TGF-β1 is closely related to the occurrence and development of tumors. A large number of previous studies have shown that melatonin can inhibit a variety of malignancies. Thus, the aim of the present study was to investigate the role of TGF-β1 in the melatonin-mediated inhibition of the proliferation of gastric cancer cells in vitro and in vivo. TGF-β1 cytokine stimulation, anti-TGF-β1 neutralizing antibody blocking, siRNA TGF-β1 and other means were utilized to explore the role of TGF-β1 during the course of anti-gastric cancer by melatonin. The results showed that melatonin upregulated the expression of TGF-β1 in tumor tissues during the process of inhibiting gastric cancer tumor growth in vivo. Melatonin inhibited the proliferation of gastric cancer cells in vitro, accompanied by increased expression of TGF-β1 in a time-dependent manner. siRNA-mediated silencing of TGF-β1 and anti-TGF-β1 neutralizing antibody completely blocked the TGF-β1 pathway, which significantly antagonized the melatonin-mediated inhibition of the growth and proliferation of gastric cancer cells, and promoted G1 phase to S phase transformation of MFC cells. Our findings suggest that TGF-β1 is involved in the regulation of the proliferation of tumor cells. One of the ways in which melatonin inhibits the proliferation of gastric cancer cells is dependent on the TGF-β1 signaling pathway.

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Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway

Cited by 50 publications

References 58 publications

Downregulation of AKT and MDM2, Melatonin Induces Apoptosis in AGS and MGC803 Cells

Downregulation of AKT and MDM2, Melatonin Induces Apoptosis in AGS and MGC803 Cells

Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation

Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo

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