4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species
4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species
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DOI：
10.1158/0008-5472.can-08-2177
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Surh, Young-Joon
中科院分区：
文献类型：
--
作者：
Park, Sin-Aye;Na, Hye-Kyung;Surh, Young-Joon
雌激素被细胞色素P450 1B 1转化为4-羟基雌二醇（4-OHE 2），这是一种推定的雌激素致癌代谢产物。这种儿茶酚雌激素代谢物被进一步氧化，通过半醌产生反应性醌。4-OHE 2与其醌型化合物之间的氧化还原循环产生活性氧物质（ROS）。ROS不仅引起DNA氧化损伤，而且促进起始细胞的肿瘤转化。在本研究中，4-OHE 2诱导人乳腺上皮细胞（MCF-10A）的锚定非依赖性集落形成。用4-OHE 2处理的MCF-10A细胞表现出细胞内ROS积累增加。抗氧化剂N-乙酰-L-半胱氨酸抑制4-OHE 2诱导的肿瘤转化。由4-OHE 2过度产生的ROS通过诱导I κ B激酶α（IKK α）和IKK β活性增加核因子-κ B（NF-κ B B）的核转位及其DNA结合。Bay 11-7082对IKK活性的抑制显著降低了4-OHE 2诱导的非锚定依赖性生长。4-OHE 2诱导的细胞外信号调节激酶和Akt的活化导致IKK活性增强和I κ B α磷酸化，从而诱导NF-κ B活化和MCF-10 A细胞的锚定非依赖性生长。总之，在4-OHE 2的氧化还原循环过程中伴随过量产生的ROS激活IKK信号传导，这可能有助于MCF-10A细胞的肿瘤转化。[Cancer Res 2009;69（6）：2416-24]
Estrogen is converted by cytochrome P450 1B1 to 4-hydroxyestradiol (4-OHE2), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE2 and its quinoid generates reactive oxygen species (ROS). ROS not only causes oxidative DNA damage but also promotes neoplastic transformation of initiated cells. In the present study, 4-OHE2 induced anchorage-independent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE2 exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-L-cysteine inhibited the neoplastic transformation induced by 4-OHE2. ROS overproduced by 4-OHE2 increased the nuclear translocation of nuclear factor-kappa B (NF-kappa B) and its DNA binding through induction of I kappa B kinase alpha (IKK alpha) and IKK beta activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE2. The 4-OHE2-induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of I kappa B alpha, thereby inducing NF-kappa B activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE2, activates IKK signaling, which may contribute to neoplastic transformation of MCF-10A cells. [Cancer Res 2009;69(6):2416-24]