KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma

Tao Ma, Harsh Patel, Savalan Babapoor-Farrokhran, Renty Franklin, Gregg L. Semenza, Akrit Sodhi, Silvia Montaner

Research output: Contribution to journalArticle

Abstract

Kaposi’s sarcoma (KS) is a vascular neoplasm caused by infection of endothelial or endothelial precursor cells with the Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV8). Research efforts have focused on defining the molecular events explaining how KSHV promotes pathological angiogenesis and KS tumor formation. mTOR/HIF-1 is a fundamental pathway driving these processes through the upregulation of angiogenic and inflammatory proteins, including VEGF, ANGPTL4, and ANGPT2. Interestingly, HIF-1 has also been implicated in the upregulation of metabolic genes associated with aerobic glycolysis and the growth of solid tumors. However, whether HIF-1 plays a role in regulating cell metabolism in KS remains unexplored. Here, we show that the HIF-1 metabolic effector, pyruvate kinase 2 (PKM2), is upregulated upon KSHV infection of endothelial cells and is necessary to maintain aerobic glycolysis in infected cells. We further demonstrate that PKM2 regulates KS angiogenic phenotype by acting as a coactivator of HIF-1 and increasing the levels of HIF-1 angiogenic factors, including VEGF. Indeed, inhibition of PKM2 expression blocked endothelial cell migration and differentiation and the angiogenic potential of KSHV-infected cells. We also investigated whether PKM2 regulates the angiogenic dysregulation induced by the KSHV-encoded G protein-coupled receptor (vGPCR), a viral oncogene that promotes Kaposi’s sarcomagenesis through the upregulation of HIF angiogenic factors. Interestingly, we found that PKM2 controls vGPCR-induced VEGF paracrine secretion and vGPCR oncogenesis. Our findings provide a molecular mechanism for how HIF-1 dysregulation fuels both angiogenesis and tumor metabolism in KS and support further investigations on therapeutic approaches targeting HIF-1 and PKM2 for KS treatment.

Original languageEnglish (US)
Pages (from-to)477-488
Number of pages12
JournalAngiogenesis
Volume18
Issue number4
DOIs
StatePublished - Oct 1 2015

Keywords

  • Angiogenesis
  • Cell metabolism
  • HHV-8
  • Human herpesvirus-8
  • Hypoxia inducible factor-1
  • KSHV
  • Kaposi’s sarcoma
  • Kaposi’s sarcoma-associated herpesvirus
  • Pyruvate kinase 2
  • VEGF

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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