Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells.
Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells.
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DOI：
10.18632/oncotarget.11817
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发表时间：
2016-10-18
期刊：
影响因子：
--
通讯作者：
Smit MJ
中科院分区：
文献类型：
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作者：
de Wit RH;Mujić-Delić A;van Senten JR;Fraile-Ramos A;Siderius M;Smit MJ
人巨细胞病毒(HCMV)编码的趋化因子受体US28通过激活多种增殖和血管生成信号通路促进肿瘤的发生。在感染后，US28以依赖于G蛋白的方式显示结构性活动和信号，劫持宿主的细胞机。在肿瘤细胞中，缺氧诱导因子-1α/丙酮酸激酶M2(HIF-1α/PKM2)轴通过支持增殖、血管生成和能量代谢重编程发挥重要作用。在这项研究中，我们发现US28信号导致了成纤维细胞和胶质母细胞瘤细胞中HIF-1α/PKM2前馈环的激活。US28的结构活性通过GαQ-、CaMKII-和Akt/mTor依赖的机制增加了HIF-1蛋白的稳定性。此外，我们还发现，在US28表达的细胞中，血管内皮生长因子和乳酸的分泌增加，与葡萄糖代谢有关的HIF-1靶基因葡萄糖转运体1(GLUT1)和3-磷酸甘油醛脱氢酶(GAPDH)上调。此外，PKM2被磷酸化，并在US28表达时发现处于肿瘤相关的二聚体状态。此外，在感染HCMV的细胞中，HIF-1活性增强，这在一定程度上是US28依赖的。最后，在抑制HIF-1α/PKM2级联后，表达US28的细胞的增殖增加被取消。这些数据突显了HIF-1α和PKM2在US28诱导的增殖、血管生成和代谢重编程中的重要性。
The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays an important role by supporting proliferation, angiogenesis and reprogramming of energy metabolism. In this study we show that US28 signaling results in activation of the HIF-1α/PKM2 feedforward loop in fibroblasts and glioblastoma cells. The constitutive activity of US28 increases HIF-1 protein stability through a Gαq-, CaMKII- and Akt/mTOR-dependent mechanism. Furthermore, we found that VEGF and lactate secretion are increased and HIF-1 target genes, glucose transporter type 1 (GLUT1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), involved in glucose metabolism, are upregulated in US28 expressing cells. In addition, PKM2 is phosphorylated and found to be in a tumor-associated dimeric state upon US28 expression. Also in HCMV-infected cells HIF-1 activity is enhanced, which in part is US28-dependent. Finally, increased proliferation of cells expressing US28 is abolished upon inhibition of the HIF-1α/PKM2 cascade. These data highlight the importance of HIF-1α and PKM2 in US28-induced proliferation, angiogenesis and metabolic reprogramming.