Induction of the hypoxia-inducible factor system by low levels of heat shock protein 90 inhibitors
Induction of the hypoxia-inducible factor system by low levels of heat shock protein 90 inhibitors
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DOI：
10.1158/0008-5472.can-05-1877
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Katschinski, DM
中科院分区：
文献类型：
--
作者：
Ibrahim, NO;Hahn, T;Katschinski, DM
异源二聚体缺氧诱导因子-1（HIF-1）参与肿瘤进展和治疗抗性的关键步骤，因此代表了一个有吸引力的抗肿瘤靶点。由于热休克蛋白90（HSP 90）在HIF-1 α蛋白稳定中起着重要作用，并且由于HSP 90抑制剂目前正在临床I期试验中进行抗癌治疗的测试，我们研究了它们作为抗HIF-1 α药物的作用。令人惊讶的是，低剂量（5-30 mnol/L）处理HeLa细胞与三种不同的HSP 90抑制剂（17-AAG，17-DMAG，格尔德霉素）增加HIF-1依赖的报告基因的活性，而较高的剂量（1-3 μ mol/L）导致缺氧诱导的HIF-1活性的降低。与这些数据一致，低剂量HSP 90抑制剂治疗分别增加和高剂量治疗降低缺氧HIF-1 α蛋白水平。HSP 90抑制剂稳定的HIF-1 α蛋白定位于细胞核。作为HSP 90调节的HIF-1活性的结果，肿瘤相关的HIF-1下游靶点碳酸酐酶IX、脯氨酰-4-羟化酶结构域蛋白3和血管内皮生长因子的水平在低剂量或高剂量治疗后分别升高或降低。在鸡胚绒毛尿囊膜血管生成试验中也观察到17-AAG对血管形成的双峰效应。总之，这些结果表明，剂量将是用HSP 90抑制剂治疗肿瘤患者的关键因素。
The heterodimeric hypoxia-inducible factor-1 (HIF-1) is involved in key steps of tumor progression and therapy resistance and thus represents an attractive antitumor target. Because heat shock protein 90 (HSP90) plays an important role in HIF-1 alpha protein stabilization and because HSP90 inhibitors are currently being tested in clinical phase I trials for anticancer treatment, we investigated their role as anti-HIF-1 alpha agents. Surprisingly, low-dose (5-30 mnol/L) treatment of HeLa cells with three different HSP90 inhibitors (17-AAG, 17-DMAG, and geldanamycin) increased HIF-1-dependent reporter gene activity, whereas higher doses (1-3 mu mol/L) resulted in a reduction of hypoxia-induced HIF-1 activity. In line with these data, low-dose treatment with HSP90 inhibitors increased and high-dose treatment reduced hypoxic HIF-1 alpha protein levels, respectively. HIF-1 alpha protein stabilized by HSP90 inhibitors localized to the nucleus. As a result of HSP90-modulated HIF-1 activity, the levels of the tumor-relevant HIF-1 downstream targets carbonic anhydrase IX, prolyl-4-hydroxylase domain protein 3, and vascular endothelial growth factor were increased or decreased after low-dose or high-dose treatment, respectively. Bimodal effects of 17-AAG on vessel formation were also seen in the chick chorioallantoic membrane angiogenesis assay. In summary, these results suggest that dosage will be a critical factor in the treatment of tumor patients with HSP90 inhibitors.