Synergistic up-regulation of Hexokinase-2, glucose transporters and angiogenic factors in pancreatic cancer cells by glucose deprivation and hypoxia
Synergistic up-regulation of Hexokinase-2, glucose transporters and angiogenic factors in pancreatic cancer cells by glucose deprivation and hypoxia
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DOI：
10.1016/j.yexcr.2007.06.013
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发表时间：
2007-09-10
影响因子：
3.7
通讯作者：
Kobayashi, Masanobu
中科院分区：
文献类型：
--
作者：
Natsuizaka, Mitsuteru;Ozasa, Mariko;Kobayashi, Masanobu
越来越多的证据表明，HIF-1是肿瘤组织对缺氧适应性反应的关键调节因子。对于这一证据，我们补充说，对葡萄糖剥夺加上缺氧的适应反应对于肿瘤微环境中肿瘤细胞的存活也是必要的，因为癌组织暴露于葡萄糖剥夺以及缺氧。我们发现，肾上腺髓质素（AM），VEGF，Glut-1，Glut-3，和Hexokinase-2的45个缺氧诱导基因的研究中表达水平较高的葡萄糖剥夺缺氧条件下比缺氧条件下。在常氧和缺氧条件下，葡萄糖剥夺激活AMPK。AMPK抑制剂化合物C可抑制缺氧条件下AM和VEGF的表达。AMPK α 1和AMPK α 2的siRNA抑制AM和VEGF的表达。因此，发现缺氧缺糖条件下的HIF-1 α蛋白水平和HIF-1的转录活性与缺氧条件下的那些相似。此外，20个人胰腺癌组织样本中的15个中的肿瘤细胞被抗磷酸化AMPK α抗体染色。因此，我们的研究结果表明，这些基因的表达增强介导的AMPK和HIF-1的激活，因此在胰腺癌的肿瘤形成中发挥了关键作用。(c)2007年爱思唯尔公司All rights reserved.
There is accumulating evidence demonstrating that HIF-1 functions as a key regulator of the adaptation responses to hypoxia in cancer tissues. To this evidence, we add that adaptation responses to glucose deprivation plus hypoxia are also necessary for the survival of tumor cells in the tumor microenvironment as cancer tissues are exposed to glucose deprivation as well as hypoxia. We found that adrenomedullin (AM), VEGF, Glut-1, Glut-3, and Hexokinase-2 among 45 hypoxia-inducible genes investigated were expressed at higher levels under glucose-deprived hypoxic conditions than under hypoxic conditions. Glucose deprivation activated the AMPK under normoxia and hypoxia. Compound C, an inhibitor of AMPK, suppressed the expressions of AM and VEGF which had already been enhanced under glucose-deprived hypoxic conditions. siRNAs for both AMPK alpha 1 and AMPK alpha 2 suppressed the expressions of AM and VEGF. HIF-1 alpha protein level and the transcriptional activity of HIF-1 under glucose-deprived hypoxic conditions were thus found to be similar to those under hypoxic conditions. Furthermore, tumor cells in 15 out of 20 human pancreatic cancer tissue specimens were stained by anti-phospho-AMPK alpha antibody. Our results thus suggest that the enhanced expressions of those genes mediated by the activation of AMPK and HIF-1 therefore play a pivotal role in the tumor formation of pancreatic cancers. (c) 2007 Elsevier Inc. All rights reserved.