Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells
Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells
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DOI：
10.1039/c2mb05486h
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Maffia, Michele
中科院分区：
文献类型：
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作者：
Vergara, Daniele;Simeone, Pasquale;Maffia, Michele
植物化学物质是一组对人类健康具有明显作用的物质。它们对癌症起始、促进和进展的性质有充分的文献记载。现在特别注意致力于更好地了解其抗癌作用的分子基础。在本工作中，我们研究了白藜芦醇对卵巢癌细胞株OVCAR-3的影响，通过蛋白质组学的方法。我们的研究结果表明，白藜芦醇下调蛋白周期蛋白D1，并在浓度依赖性的方式，蛋白激酶B（Akt）和糖原合成酶激酶-3 β（GSK-3 β）的磷酸化水平。这些激酶的去磷酸化可能是治疗后观察到的细胞周期蛋白D1水平降低的原因。我们还发现，白藜芦醇降低细胞外信号调节激酶（ERK）1/2的磷酸化水平。磷脂酰肌醇3-激酶（PI 3 K）和ERK的化学抑制剂都增加了白藜芦醇的体外治疗效果。此外，白藜芦醇对来自卵巢癌患者腹水的培养细胞和一组人类癌细胞系中的AKT磷酸化具有抑制作用。因此，白藜芦醇在人卵巢癌细胞系中显示出抗肿瘤活性，靶向参与细胞增殖和耐药性的信号通路。
Phytochemicals constitute a heterogeneous group of substances with an evident role in human health. Their properties on cancer initiation, promotion and progression are well documented. Particular attention is now devoted to better understand the molecular basis of their anticancer action. In the present work, we studied the effect of resveratrol on the ovarian cancer cell line OVCAR-3 by a proteomic approach. Our findings demonstrate that resveratrol down-regulates the protein cyclin D1 and, in a concentration dependent manner, the phosphorylation levels of protein kinase B (Akt) and glycogen synthase kinase-3 beta (GSK-3 beta). The dephosphorylation of these kinases could be responsible for the decreased cyclin D1 levels observed after treatment. We also showed that resveratrol reduces phosphorylation levels of the extracellular signal-regulated kinase (ERK) 1/2. Chemical inhibitors of phosphatidylinositol 3-kinase (PI3K) and ERK both increased the in vitro therapeutic efficacy of resveratrol. Moreover, resveratrol had an inhibitory effect on the AKT phosphorylation in cultured cells derived from the ascites of ovarian cancer patients and in a panel of human cancer cell lines. Thus, resveratrol shows antitumor activity in human ovarian cancer cell lines targeting signalling pathway involved in cell proliferation and drug-resistance.