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

Abstract

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-

Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells

“…Melatonin has been widely reported to modulate Akt in both tumoral and nontumoral cells [ 49 , 50 , 51 , 52 ]. In human melanoma cells (SK-MEL-1), Perdomo et al [ 53 ] demonstrate that, as melatonin promotes GSK-3β dephosphorylation at serine 9 via Akt pathway inhibition, the activation of GSK-3β by melatonin results in an increase in ROS production ( Figure 2 ).…”

An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress

“…As a powerful antioxidant melatonin inhibits ROS-induced activation of extracellular-regulated protein kinases (ERKs) and Akt pathways which are involved in the cancer cell survivor; inactivation of ROS-dependent Akt signaling contributes to the down-regulation of cyclin D1, PCNA, and Bcl-2 and up-regulation of Bax in cancer cells [ 48 ]. Inhibition of MDM2 expression is a mechanism by which melatonin induces apoptosis through upregulating the activity of caspase-3 and -9; MDM2 is an E3 ubiquitin ligase, which negatively regulates the p53 tumor suppressor [ 112 , 113 ]. Under hypoxic conditions, tumor cells become resistant to TRAIL-induced cell apoptosis; this contributes to the up-regulation of anti-apoptotic protein expression and reduction of pro-apoptotic protein expression.…”

“…D1, PCNA, and Bcl-2 and up-regulation of Bax in cancer cells [48]. Inhibition of MDM2 expression is a mechanism by which melatonin induces apoptosis through upregulating the activity of caspase-3 and -9; MDM2 is an E3 ubiquitin ligase, which negatively regulates the p53 tumor suppressor [112,113]. Under hypoxic conditions, tumor cells become resistant to TRAIL-induced cell apoptosis; this contributes to the up-regulation of anti-apoptotic protein expression and reduction of pro-apoptotic protein expression.…”

Use of Melatonin in Cancer Treatment: Where Are We?

“…In the tumor promotion phase, tumor cells are known to downregulate tumor suppressor genes that would trigger the apoptosis pathway, while this process could be rescued by melatonin. For instance, in gastric cancer cells, melatonin induced apoptosis by downregulating the mouse double minute 2 homolog (MDM2) [ 28 ]. It also induced apoptosis by suppressing o-GlcNAcylation of cyclin-dependent-like kinase 5 (CDK5) in bladder cancer cells [ 29 ].…”