SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression
SNS-032 prevents hypoxia-mediated glioblastoma cell invasion by inhibiting hypoxia inducible factor-1α expression
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DOI：
10.3892/ijo_00000231
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发表时间：
2009-04-01
影响因子：
5.2
通讯作者：
Saha, Debabrata
中科院分区：
文献类型：
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作者：
Ali, M. Aktar;Reis, Aimee;Saha, Debabrata
缺氧和缺氧诱导因子-1 α（HIF-1 α）在胶质母细胞瘤（GBM）中起关键作用，胶质母细胞瘤（GBM）的特征是高度侵袭性和广泛的细胞侵入邻近正常脑组织。本研究旨在探讨新型氨基噻唑类化合物SNS-032在缺氧条件下对胶质母细胞瘤细胞侵袭能力的影响。SNS-032是细胞周期蛋白依赖性激酶2、7和9的有效和选择性抑制剂，并抑制细胞周期和转录。我们分析了SNS-032（0.5 μ M）对HIF-1 α表达及其主要的反式调节因子（包括考克斯-2、VEGF、MMP-2和uPAR）的影响，这些因子参与肿瘤缺氧时的细胞侵袭。我们的观察结果表明SNS-032：i）抑制缺氧诱导的U87 MG细胞侵袭，并且在所有测试的其他抑制剂中，SNS-032是最有效的，ii）阻断U87 MG细胞中响应缺氧的HIF-1 α介导的考克斯-2、MMP-2、VEGF和uPAR表达的转录，iii）通过蛋白酶体非依赖性途径阻断HIF-1 α表达。该作用与用HIF-1 α siRNA观察到的作用相似，所述HIF-1 α siRNA通过阻断HIF-1 α表达及其下游效应物来防止细胞侵袭。综上所述，我们的数据表明SNS-032通过阻断HIF-1 α及其反式调节因子的表达来防止缺氧介导的U87 MG细胞侵袭。我们的研究结果提供了一个机会，在控制高度侵袭性肿瘤，如胶质母细胞瘤使用这类新的化合物。
Hypoxia and hypoxia inducible factor-1 alpha (HIF-1 alpha) play a critical role in glioblastoma (GBM) which is characterized by highly aggressive and widespread cell invasion into adjacent normal brain tissue. The purpose of this study wall to investigate the effect of the novel aminothiazole compound SNS-032 in glioblastoma cell invasion under hypoxic condition. SNS-032 is a potent and selective inhibitor of cyclin-dependent kinases 2, 7 and 9 and inhibits both cell cycle and transcription. We analyzed the effect of SNS-032 (0.5 mu M) on HIF-1 alpha expression and its major trans-regulating factors including COX-2, VEGF, MMP-2 and uPAR that are involved in cellular invasion in tumor hypoxia. Our observations demonstrate SNS-032: i) inhibited hypoxia-induced U87MG cell invasion and among all the other inhibitors tested, SNS-032 is the most effective, ii) blocked HIF-1 alpha mediated transcription of COX-2, MMP-2, VEGF and uPAR expression in U87MG cells in response to hypoxia, iii) blocked HIF-1 alpha expression by a proteasome independent pathway. The effects were similar to those observed with HIF-1 alpha siRNA which prevented cellular invasion by blocking HIF-1 alpha expression and its downstream effectors. Taken together, our data suggest that SNS-032 prevents hypoxia-mediated U87MG cell invasion by blocking the expression of HIF-1 alpha and its trans-regulating factors. Our results present an opportunity in controlling highly invasive tumors such as glioblastoma using this novel class of compounds.