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

Globally, gastric cancer (GC) is one of the most common types of cancer and the third leading cause of cancer-related death. In China, gastric and liver cancers have the highest mortality rates. Melatonin, also known as N-acetyl-5-methoxytryptamine, is a hormone that is produced by the pineal gland in animals and regulates sleep and wakefulness. Melatonin has been shown to inhibit various carcinomas, including GC. There are many different hypotheses to explain the anticancer effects of melatonin, including stimulation of apoptosis, inhibition of cell growth, regulation of anticancer immunity, induction of free-radical scavenging, and the competitive inhibition of estrogen. However, the underlying mechanism by which these effects are elicited remains elusive. The aim of the present study was to investigate the effects of melatonin on human GC cells and determine the underlying molecular mechanism. We treated SGC-7901 GC cells with melatonin and analyzed the resulting protein changes using protein chip technology. Several proteins related to cell apoptosis and proliferation were identified and further tested in SGC-7901 GC cells. We found that melatonin induced cell cycle arrest and the downregulation of CDC25A, phospho-CDC25A (at Ser75), p21 (p21Cip1/p21Waf1) and phospho-p21 (at Thr145). Melatonin also induced upregulation of Bax, downregulation of Bcl-xL, an increase in cleaved caspase-9 level and activation of caspase-3, which confirmed the involvement of the mitochondria in melatonin-induced apoptosis. Upstream regulators of the above proteins, MDM2, phospho-MDM2 (at Ser166) and AKT, phospho-AKT (at Thr308) were all attenuated by melatonin, which led to an increase in p53. The present study demonstrated that the oncostatic effects of melatonin on SGC-7901 GC cells are mediated via the blockade of the AKT/MDM2 intracellular pathway.

在全球范围内，胃癌（GC）是最常见的癌症类型之一，也是癌症相关死亡的第三大原因。在中国，胃癌和肝癌的死亡率最高。褪黑素，又称N - 乙酰 - 5 - 甲氧基色胺，是一种由动物松果体产生的激素，可调节睡眠和觉醒。褪黑素已被证明能抑制多种癌症，包括胃癌。有许多不同的假说用于解释褪黑素的抗癌作用，包括刺激细胞凋亡、抑制细胞生长、调节抗癌免疫、诱导自由基清除以及对雌激素的竞争性抑制。然而，引发这些作用的潜在机制仍然不清楚。本研究的目的是探讨褪黑素对人胃癌细胞的影响并确定潜在的分子机制。我们用褪黑素处理SGC - 7901胃癌细胞，并使用蛋白质芯片技术分析由此产生的蛋白质变化。鉴定出了几种与细胞凋亡和增殖相关的蛋白质，并在SGC - 7901胃癌细胞中进一步进行了检测。我们发现褪黑素诱导细胞周期停滞，CDC25A、磷酸化CDC25A（在Ser75位点）、p21（p21Cip1 / p21Waf1）和磷酸化p21（在Thr145位点）下调。褪黑素还诱导Bax上调、Bcl - xL下调、切割后的caspase - 9水平升高以及caspase - 3激活，这证实了线粒体参与了褪黑素诱导的细胞凋亡。上述蛋白质的上游调节因子MDM2、磷酸化MDM2（在Ser166位点）以及AKT、磷酸化AKT（在Thr308位点）都被褪黑素减弱，从而导致p53增加。本研究表明，褪黑素对SGC - 7901胃癌细胞的抑癌作用是通过阻断AKT / MDM2细胞内通路介导的。