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白藜芦醇通过 SIRT1 依赖性 AMPK 激活调节肿瘤细胞增殖和蛋白质翻译。

Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation.

机构信息

The PhD Program for Cancer Biology and Drug Discovery, College of Pharmacy, China Medical University, Taichung, Taiwan.

出版信息

J Agric Food Chem. 2010 Feb 10;58(3):1584-92. doi: 10.1021/jf9035782.

DOI:10.1021/jf9035782
PMID:19928762
Abstract

Resveratrol functions as an agonist for estrogen receptor (ER)-mediated transcription. However, other researchers have reported that resveratrol decreases proliferation of breast cancer cells that are either ER-positive or ER-negative, which suggests that the interaction of resveratrol with the ER may not fully explain its inhibitory effect on proliferation. Similar to those effects associated with caloric restriction (CR), resveratrol has multiple beneficial activities, such as increased life span and delay in the onset of diseases associated with aging. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and antiproliferative properties of resveratrol has led us to hypothesize that resveratrol activity might have an important role in the activation of AMPK. Here, we show that resveratrol activated AMPK in both ER-positive and ER-negative breast cancer cells. Once activated, AMPK inhibited 4E-BP1 signaling and mRNA translation via mammalian target of rapamycin (mTOR). Moreover, we also found that AMPK activity mediated by resveratrol in cancer cells was due to inducing the expression of Sirtuin type 1 (SIRT1) via elevation in the cellular NAD(+)/NADH in ER-positive cells. To our knowledge, we demonstrate here for the first time that resveratrol induces the expression of SIRT1 protein in human cancer cells. These observations raise the possibility that SIRT1 functions as a novel upstream regulator for AMPK signaling and may additionally modulate tumor cell proliferation. Targeting SIRT1/AMPK signaling by resveratrol may have potential therapeutic implications for cancer and age-related diseases.

摘要

白藜芦醇作为雌激素受体 (ER) 介导转录的激动剂发挥作用。然而,其他研究人员报告说,白藜芦醇降低了无论是 ER 阳性还是 ER 阴性的乳腺癌细胞的增殖,这表明白藜芦醇与 ER 的相互作用可能无法完全解释其对增殖的抑制作用。与与热量限制 (CR) 相关的那些作用相似,白藜芦醇具有多种有益的活性,例如延长寿命和延迟与衰老相关的疾病的发作。被认为在 CR 期间被激活的一种关键酶是 AMP 激活的蛋白激酶 (AMPK),它是细胞能量水平的传感器。激活的 AMPK 通过抑制非必需的能量消耗以及 CR 模拟物和白藜芦醇的抗增殖特性,使我们假设白藜芦醇的活性可能在 AMPK 的激活中起重要作用。在这里,我们表明白藜芦醇在 ER 阳性和 ER 阴性乳腺癌细胞中均可激活 AMPK。一旦被激活,AMPK 通过雷帕霉素 (mTOR) 的哺乳动物靶标 (mTOR) 抑制 4E-BP1 信号和 mRNA 翻译。此外,我们还发现,白藜芦醇在癌细胞中通过 AMPK 活性是由于通过提高细胞 NAD(+)/NADH 诱导 Sirtuin 类型 1 (SIRT1) 的表达而在 ER 阳性细胞中。据我们所知,我们在这里首次证明白藜芦醇在人类癌细胞中诱导 SIRT1 蛋白的表达。这些观察结果提出了这样一种可能性,即 SIRT1 作为 AMPK 信号的新型上游调节剂发挥作用,并且可能另外调节肿瘤细胞增殖。通过白藜芦醇靶向 SIRT1/AMPK 信号可能对癌症和与年龄相关的疾病具有潜在的治疗意义。

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