Multiple receptor tyrosine kinases regulate HIF-1α and HIF-2α in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors
Multiple receptor tyrosine kinases regulate HIF-1α and HIF-2α in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors
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DOI：
10.1038/onc.2010.60
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发表时间：
2010-05-01
期刊：
影响因子：
8
通讯作者：
Heymach, J. V.
中科院分区：
文献类型：
--
作者：
Nilsson, M. B.;Zage, P. E.;Heymach, J. V.
晚期神经母细胞瘤患儿需要新的治疗方法。对神经母细胞瘤细胞的研究表明，存在一种缺氧驱动的血管内皮生长因子（VEGF）/VEGF受体（VEGFR）-1自分泌环，可调节缺氧诱导因子-1α（HIF - 1α）。其他受体酪氨酸激酶（RTKs）是否能够调节HIF - 1α水平以及是否也能调节HIF - 2α在很大程度上尚不清楚。我们评估了神经母细胞瘤细胞系中各种RTKs的表达情况。尽管细胞系在VEGFR - 1、-3、c - Kit和RET的表达上存在异质性，但大多数细胞表达血小板衍生生长因子受体（PDGFR）-α和-β。配体诱导的多种RTKs激活会上调HIF - 1α水平，而单独激活VEGFR - 1会上调HIF - 2α。多靶点酪氨酸激酶抑制剂舒尼替尼通过影响mRNA水平和蛋白质稳定性的机制，降低了缺氧诱导的HIF - 1α和HIF - 2α的升高。此外，舒尼替尼和索拉非尼在体外对肿瘤细胞的活力有直接影响。在神经母细胞瘤异种移植模型中，舒尼替尼对肿瘤生长的抑制与抑制血管生成和降低HIF - 1α水平有关。这些发现表明，多种RTKs可能在常氧和缺氧条件下调节HIF轴，并提示多激酶抑制剂可能不仅通过对内皮细胞的直接作用，还通过阻断缺氧和配体诱导的HIF - 1α和HIF - 2α的代偿性变化而发挥抗血管生成作用。《癌基因》（2010年）29卷，2938 - 2949页；doi:10.1038/onc.2010.60；2010年3月8日在线发表
Novel treatment approaches are needed for children with advanced neuroblastoma. Studies with neuroblastoma cells have indicated the presence of a hypoxiadriven vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-1 autocrine loop modulating hypoxia-inducible factor-1alpha (HIF-1 alpha). Whether other receptor tyrosine kinases (RTKs) are capable of modulating HIF-1 alpha levels and whether RTKs can regulate HIF-2 alpha as well is largely unknown. We evaluated neuroblastoma cell lines for expression of various RTKs. Although cell lines were heterogeneous in the expression of VEGFR-1, -3, c-Kit and RET, most cells expressed PDGFR-alpha and -beta. Ligand-induced activation of multiple RTKs upregulated HIF-1 alpha levels, whereas activation of VEGFR-1 alone upregulated HIF-2 alpha. Multitargeted tyrosine kinase inhibitor sunitinib reduced hypoxia-induced rises in HIF-1 alpha and HIF-2 alpha through mechanisms involving effects on both mRNA levels and protein stability. In addition, sunitinib and sorafenib had direct effects on tumor cell viability in vitro. In a neuroblastoma xenograft model, tumor growth inhibition by sunitinib was associated with inhibition of angiogenesis and reduced HIF-1 alpha levels. These findings show that multiple RTKs may regulate the HIF axis in normoxia and hypoxia and suggest that multikinase inhibitors may exert antiangiogenic effects not only by direct effects on endothelial cells, but also by blocking compensatory hypoxia- and ligand-induced changes in HIF-1 alpha and HIF-2 alpha. Oncogene (2010) 29, 2938-2949; doi:10.1038/onc.2010.60; published online 8 March 2010