Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells

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 -