TY - JOUR
T1 - Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells
AU - de Wit, Raymond H
AU - Mujić-Delić, Azra
AU - van Senten, Jeffrey R
AU - Fraile-Ramos, Alberto
AU - Siderius, Marco
AU - Smit, Martine J
PY - 2016/10/18
Y1 - 2016/10/18
N2 - 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 Gaq-, 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.
AB - 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 Gaq-, 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.
KW - Animals
KW - Carrier Proteins/genetics
KW - Cell Line, Tumor
KW - Cell Transformation, Neoplastic/genetics
KW - Cells, Cultured
KW - Cytomegalovirus/physiology
KW - Fibroblasts/metabolism
KW - Glioblastoma/genetics
KW - HEK293 Cells
KW - Host-Pathogen Interactions
KW - Humans
KW - Hypoxia-Inducible Factor 1, alpha Subunit/genetics
KW - Male
KW - Membrane Proteins/genetics
KW - Mice
KW - NIH 3T3 Cells
KW - Receptors, Chemokine/genetics
KW - Signal Transduction
KW - Thyroid Hormones/genetics
KW - Viral Proteins/genetics
U2 - 10.18632/oncotarget.11817
DO - 10.18632/oncotarget.11817
M3 - Journal article
C2 - 27602585
SN - 1949-2553
VL - 7
SP - 67966
EP - 67985
JO - OncoTarget
JF - OncoTarget
IS - 42
ER -