Gao Ning, Shen Liqin, Zhang Zhuo, Leonard Stephen S, He Hengjun, Zhang Xue-Guang, Shi Xianglin, Jiang Bing-Hua
Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA.
Mol Cell Biochem. 2004 Jan;255(1-2):33-45. doi: 10.1023/b:mcbi.0000007259.65742.16.
Arsenite is widely distributed environmental toxicant in water, food and air. It is a known human carcinogen, which is strongly associated with human cancers originated from liver, nasal cavity, lung, skin, bladder, kidney, and prostate. In this study, we investigated whether arsenite induces expression of hypoxia-inducible factor 1 (HIF-1). HIF-1 is a heterodimeric basic helix-loop-helix transcription factor, composed of HIF-1alpha and HIF-1beta/ARNT subunits; and is involved in tumor growth and angiogenesis. Here we demonstrate that arsenite induces the expression of HIF-1alpha but not HIF-1beta subunit in DU145 human prostate carcinoma cells. Arsenite also increases the expression of VEGF through the induction of HIF-1. We also found that arsenite activates PI3K and Akt that are required for arsenite-induced expression of HIF-1alpha and VEGF. The induction of HIF-1 and VEGF by arsenite can not be inhibited by MAP kinase inhibitors. Arsenite causes production of reactive oxygen species (ROS). The major species of ROS required for the induction of HIF-1 and VEGF is H2O2. These data indicate that the arsenite-induced activation of PI3K/Akt signaling and the expression of HIF-1 and VEGF through the generation of ROS could be an important mechanism in the arsenite-induced carcinogenesis.
亚砷酸盐是一种广泛存在于水、食物和空气中的环境毒物。它是一种已知的人类致癌物，与源自肝脏、鼻腔、肺、皮肤、膀胱、肾脏和前列腺的人类癌症密切相关。在本研究中，我们调查了亚砷酸盐是否诱导缺氧诱导因子1（HIF-1）的表达。HIF-1是一种异二聚体碱性螺旋-环-螺旋转录因子，由HIF-1α和HIF-1β/ARNT亚基组成；并参与肿瘤生长和血管生成。在此我们证明，亚砷酸盐在DU145人前列腺癌细胞中诱导HIF-1α亚基的表达，但不诱导HIF-1β亚基的表达。亚砷酸盐还通过诱导HIF-1增加血管内皮生长因子（VEGF）的表达。我们还发现，亚砷酸盐激活PI3K和Akt，而PI3K和Akt是亚砷酸盐诱导HIF-1α和VEGF表达所必需的。亚砷酸盐对HIF-1和VEGF的诱导作用不能被丝裂原活化蛋白激酶（MAP）抑制剂抑制。亚砷酸盐会导致活性氧（ROS）的产生。诱导HIF-1和VEGF所需的主要ROS种类是过氧化氢（H2O2）。这些数据表明，亚砷酸盐通过ROS的产生激活PI3K/Akt信号通路以及诱导HIF-1和VEGF的表达可能是亚砷酸盐诱导致癌作用的重要机制。
