Hypoxia inducing factor-1α regulates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in tumor cells exposed to hypoxia
Hypoxia inducing factor-1α regulates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in tumor cells exposed to hypoxia
复制标题
DOI：
10.1016/j.bbrc.2010.07.082
复制
发表时间：
2010-08-27
影响因子：
3.1
通讯作者：
Lee, You-Jin
中科院分区：
文献类型：
--
作者：
Jeong, Jae-Kyo;Moon, Myung-Hee;Lee, You-Jin
缺氧是一种常见的环境应激。特别是，快速生长的实体瘤的中心容易暴露于缺氧条件。众所周知，缺氧会减弱对放疗和化疗的治疗反应，包括肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）蛋白。HIF-1 α是低氧反应的关键介质。然而，关于缺氧诱导因子-1 α（HIF-1 α）对缺氧抑制TRAIL介导的细胞凋亡的功能知之甚少。在这项研究中，我们研究了缺氧抑制TRAIL介导的细胞凋亡是否可以通过调节HIF-1 α蛋白来调节。缺氧和DEF诱导的HIF-1 α激活抑制了SK-N-SH、HeLa、A549和SNU-638细胞中TRAIL介导的凋亡。此外，包括DOX在内的HIF-1 α灭活剂增加了暴露于缺氧的肿瘤细胞对TRAIL蛋白的敏感性。此外，使用慢病毒RNA干扰敲低HIF-1 α使肿瘤细胞在缺氧条件下对TRAIL介导的细胞死亡敏感。总之，这些结果表明HIF-1 α失活增加了缺氧诱导的TRAIL耐药肿瘤细胞中的TRAIL敏感性，并且还表明HIF-1 α抑制剂可能在与TRAIL联合治疗中对缺氧肿瘤细胞有益。(C)2010年爱思唯尔公司All rights reserved.
Hypoxia is a common environmental stress. Particularly, the center of rapidly-growing solid tumors is easily exposed to hypoxic conditions. Hypoxia is well known to attenuate the therapeutic response to radio and chemotherapies including tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) protein. HIF-1 alpha is a critical mediator of the hypoxic response. However, little is known about the function of hypoxia-inducible factor-1 alpha (HIF-1 alpha) on hypoxic inhibition of TRAIL-mediated apoptosis. In this study, we investigated whether hypoxic inhibition of TRAIL-mediated apoptosis can be regulated by modulating HIF-1 alpha protein. Hypoxia- and DEF-induced HIF-1 alpha activation inhibited the TRAIL-mediated apoptosis in SK-N-SH, HeLa, A549 and SNU-638 cells. And also, HIF-1 alpha inactivating reagents including DOX increased the sensitivity to TRAIL protein in tumor cells exposed to hypoxia. Furthermore, knock-down of HIF-1 alpha using lentiviral RNA interference sensitized tumor cells to TRAIL-mediated cell death under hypoxic condition. Taken together, these results indicate that HIF-1 alpha inactivation increased TRAIL sensitivity in hypoxia-induced TRAIL-resistant tumor cells and also suggest that HIF-1 alpha inhibitors may have benefits in combination therapy with TRAIL against hypoxic tumor cells. (C) 2010 Elsevier Inc. All rights reserved.