HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression.
HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression.
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DOI：
10.1186/1471-2407-10-605
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发表时间：
2010-11-04
期刊：
影响因子：
3.8
通讯作者：
Vordermark D
中科院分区：
文献类型：
--
作者：
Kessler J;Hahnel A;Wichmann H;Rot S;Kappler M;Bache M;Vordermark D
缺氧诱导HIF-1通路的激活，是恶性胶质瘤的基本特征。缺氧与肿瘤进展、治疗抵抗和不良预后有关。然而，HIF-1α抑制剂对恶性胶质瘤放射抵抗性的影响尚不清楚。在本研究中，我们研究了HIF-1α抑制对U251 MG和U343 MG胶质瘤细胞的存活和放射敏感性的影响，使用两种不同的策略。通过靶向HIF-1α的siRNA或通过chetomin（HIF-1α和p300之间相互作用的破坏剂）实现HIF-1α抑制。通过实时定量PCR和HIF-1α和CA 9表达水平的Western印迹分析监测HIF-1通路的抑制。研究了CA 9表达作为HIF-1抑制功效的潜在指标，并且在常氧（2-10戈伊）或低氧（2-15戈伊）条件下照射后通过克隆形成测定法测定恶性胶质瘤细胞系的放射敏感性。虽然siRNA和chetomin表现出不同的作用模式，但两者都减弱了恶性胶质瘤细胞系U251 MG（DMF 10：1.35和1.18）和U343 MG（DMF 10：1.78和1.48）的缺氧诱导的辐射抗性。然而，siRNA和chetomin在常氧条件下对U251 MG（DMF 10：0.86和1.35）和U343 MG（DMF 10：1.33和1.02）细胞的放射敏感性表现出不同的影响。这项体外研究的结果表明，抑制HIF-1α是一种有前途的策略，使人类恶性胶质瘤对放射治疗敏感，CA 9可以作为有效的HIF-1相关放射增敏的指标。
Hypoxia induces activation of the HIF-1 pathway and is an essential characteristic of malignant gliomas. Hypoxia has been linked to tumor progression, therapy resistance and poor prognosis. However, little is known about the impact of HIF-1α inhibition on radioresistance of malignant glioma. In this study, we investigated the effects of the inhibition of HIF-1α on cell survival and radiosensitivity in U251MG and U343MG glioma cells, using two different strategies. HIF-1α inhibition was achieved by siRNA targeting of HIF-1α or via chetomin, a disruptor of interactions between HIF-1α and p300. The inhibition of the HIF-1 pathway was monitored by quantitative real-time PCR and Western blot analyses of the expression levels of HIF-1α and CA9. CA9 expression was investigated as a potential indicator of the efficacy of HIF-1 inhibition and the resulting radiosensitivity of malignant glioma cell lines was determined by clonogenic assay after irradiation under normoxic (2-10 Gy) or hypoxic (2-15 Gy) conditions. Although siRNA and chetomin show distinct modes of action, both attenuated the hypoxia-induced radioresistance of malignant glioma cell lines U251MG (DMF10: 1.35 and 1.18) and U343MG (DMF10: 1.78 and 1.48). However, siRNA and chetomin showed diverse effects on radiosensitivity under normoxic conditions in U251MG (DMF10: 0.86 and 1.35) and U343MG (DMF10: 1.33 and 1.02) cells. Results from this in vitro study suggest that inhibition of HIF-1α is a promising strategy to sensitize human malignant gliomas to radiotherapy and that CA9 could serve as an indicator of effective HIF-1-related radiosensitization.
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