Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1
Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1
复制标题
DOI：
10.1152/ajpcell.00075.2007
复制
发表时间：
2007-07-01
影响因子：
5.5
通讯作者：
Illsley, Nicholas P.
中科院分区：
文献类型：
--
作者：
Baumann, Marc U.;Zamudio, Stacy;Illsley, Nicholas P.
胎盘缺氧与妊娠病理学有关，包括胎儿生长受限和先兆子痫;然而，滋养层细胞对缺氧的反应机制尚未得到充分研究。葡萄糖转运是胎儿胎盘生长的关键过程，在许多细胞类型中被缺氧上调。我们研究了缺氧对BeWo绒毛膜癌细胞、滋养层细胞模型和人胎盘绒毛组织外植体中滋养层葡萄糖转运蛋白（GLUT）表达和活性的调节作用。BeWo细胞中GLUT 1的表达被缺氧诱导化学试剂去铁胺和氯化钴上调。氧张力的降低导致GLUT 1和GLUT 3表达的剂量依赖性增加。细胞暴露于缺氧条件下也导致跨上皮葡萄糖转运增加。缺氧诱导因子（HIF）-1的作用由缺氧导致的HIF-1 α的增加和用MG-132（一种增加HIF-1水平的蛋白酶体抑制剂）治疗BeWo后GLUT 1表达的增加提出。HIF-1的功能在GLUT 1和GLUT 3的缺氧上调被反义HIF-1 α抑制的实验中得到证实。与BeWo细胞相反，缺氧使外植体中GLUT 1表达的增加最小;然而，用MG-132处理确实上调合胞基底膜GLUT 1。我们的研究结果表明，GLUT通过缺氧通过HIF-1介导的途径在滋养层细胞中上调，并表明，GLUT在体内对缺氧的反应不仅取决于低氧张力，而且还取决于调节HIF-1水平的其他因素。
Placental hypoxia has been implicated in pregnancy pathologies, including fetal growth restriction and preeclampsia; however, the mechanism by which the trophoblast cell responds to hypoxia has not been adequately explored. Glucose transport, a process crucial to fetoplacental growth, is upregulated by hypoxia in a number of cell types. We investigated the effects of hypoxia on the regulation of trophoblast glucose transporter (GLUT) expression and activity in BeWo choriocarcinoma cells, a trophoblast cell model, and human placental villous tissue explants. GLUT1 expression in BeWo cells was upregulated by the hypoxia-inducing chemical agents desferroxamine and cobalt chloride. Reductions in oxygen tension resulted in dose-dependent increases in GLUT1 and GLUT3 expression. Exposure of cells to hypoxic conditions also resulted in an increase in transepithelial glucose transport. A role for hypoxia-inducible factor (HIF)-1 was suggested by the increase in HIF-1 alpha as a result of hypoxia and by the increase in GLUT1 expression following treatment of BeWo with MG-132, a proteasomal inhibitor that increases HIF-1 levels. The function of HIF-1 was confirmed in experiments where the hypoxic upregulation of GLUT1 and GLUT3 was inhibited by antisense HIF-1 alpha. In contrast to BeWo cells, hypoxia produced minimal increases in GLUT1 expression in explants; however, treatment with MG-132 did upregulate syncytial basal membrane GLUT1. Our results show that GLUTs are upregulated by hypoxia via a HIF-1-mediated pathway in trophoblast cells and suggest that the GLUT response to hypoxia in vivo will be determined not only by low oxygen tension but also by other factors that modulate HIF-1 levels.