The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells
The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells
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DOI：
10.4161/cc.8.1.7499
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发表时间：
2009-01-01
期刊：
影响因子：
4.3
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
--
作者：
Vazquez-Martin, Alejandro;Oliveras-Ferraros, Cristina;Menendez, Javier A.
人群研究显示，使用抗糖尿病药物二甲双胍治疗与降低乳腺癌风险显著相关。动物研究表明，二甲双胍可抑制携带HER 2癌基因的转基因雌性小鼠乳腺癌的发生，但不能抑制自发性肿瘤的发生。我们在此证明，HER 2癌蛋白本身可能是二甲双胍抗乳腺癌作用的关键细胞靶点。首先，HER 2癌基因的异位过表达显著增强二甲双胍诱导的乳腺癌细胞生长抑制。其次，二甲双胍治疗以剂量和时间依赖性方式大幅下调HER 2蛋白水平（降低高达85%）。二甲双胍诱导的HER 2抑制发生与导致HER 2过表达的分子机制无关（即，由病毒启动子外源驱动的人HER 2 cDNA和天然存在的内源HER 2基因扩增）。从机制上讲，二甲双胍诱导的HER 2过表达抑制似乎是通过直接（AMPK非依赖性）抑制p70 S6 K1活性而发生的。化合物C和小干扰RNA（siRNA）诱导的AMPK活性/表达的阻断不能阻止二甲双胍的抗HER 2作用，而暴露于AMP类似物AICAR后AMPK超活化不足以下调HER 2表达。用p70 S6 K1 siRNA转染的HER 2阳性乳腺癌细胞变得对二甲双胍诱导的HER 2抑制完全难治。值得注意的是，与阻断活性氧（ROS）产生的试剂共孵育（例如，例如，在一个实施例中，N-乙酰半胱氨酸）显著增强二甲双胍降低HER 2表达的能力。从化学预防的角度来看，这些发现共同表明二甲双胍可能主要限于HER 2阳性乳腺癌亚型发挥保护作用。从干预的角度来看，存在/不存在的分子标志，如HER 2过表达和/或p70 S6 K1超活化可能会决定在二甲双胍为基础的治疗早期乳腺癌的替代反应。mTOR/p70 S6 K1-感应ROS状态在介导二甲双胍的抗癌作用中的重要性可能代表了以前未被认识到的连接其抗衰老和抗癌作用的分子联系。
Population studies have revealed that treatment with the antidiabetic drug metformin significantly associates with reduced breast cancer risk. Animal studies have shown that metformin suppresses the development of mammary carcinomas in transgenic female mice carrying a HER2 oncogene, but not that of spontaneous tumors. We herein demonstrate that HER2 oncoprotein itself may represent a key cellular target involved in the anti-breast cancer actions of metformin. First, ectopical overexpression of HER2 oncogene significantly enhances metformin-induced breast cancer cell growth inhibition. Second, metformin treatment drastically downregulates HER2 protein levels (up to 85% reduction) in a dose- and time-dependent manner. Metformin-induced inhibition of HER2 take places regardless the molecular mechanism contributing to HER2 overexpression (i.e., human HER2 cDNA exogenously driven by a viral promoter and naturally occurring endogenous HER2 gene amplification). Mechanistically, metformin-induced suppression of HER2 overexpression appears to occur via direct (AMPK-independent) inhibition of p70S6K1 activity. Compound C- and small interference RNA (siRNA)induced blockade of AMPK activity/expression fail to prevent the anti-HER2 effect of metformin while AMPK hyperactivation following exposure to the AMP analog AICAR is not sufficient to downregulate HER2 expression. HER2-positive breast cancer cells transfected with p70S6K1 siRNA become completely refractory to metformin-induced HER2 suppression. Of note, co-incubation with agents that block reactive oxygen species (ROS) production (e. g., N-acetylcisteine) dramatically enhanced the ability of metformin to decrease HER2 expression. From the perspective of chemoprevention, these findings altogether suggest that metformin might exert a protective mostly confined to the HER2-positive breast cancer subtype. From the perspective of intervention, the presence/absence of molecular hallmarks such as HER2 overexpression and/or p70S6K1 hyperactivation might dictate alternative responses in metformin-based treatment of early breast cancer. The importance of mTOR/p70S6K1-sensed ROS status at mediating the anti-oncogenic effects of metformin might represent a previously unrecognized linkage molecularly connecting its anti-aging and anti-cancer actions.