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

Oncotarget. 2016 Oct 18;7(42):67966-67985. doi: 10.18632/oncotarget.11817.

Abstract

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.

Keywords: G protein-coupled receptor (GPCR); chemokine; glioblastoma; human cytomegalovirus (HCMV); hypoxia-inducible factor (HIF).

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Cytomegalovirus / physiology
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / virology
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • NIH 3T3 Cells
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Signal Transduction*
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Carrier Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • Receptors, Chemokine
  • Thyroid Hormones
  • US28 receptor, Cytomegalovirus
  • Viral Proteins
  • thyroid hormone-binding proteins