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

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.

• Authors: Tao Ma, Harsh Patel, Savalan Babapoor-Farrokhran, Renty Franklin, Gregg L Semenza, Akrit Sodhi, Silvia Montaner
• Journal: Angiogenesis (Angiogenesis) Vol. 18 Issue 4 Pg. 477-88 (Oct 2015) ISSN: 1573-7209 [Electronic] Germany
• PMID: 26092770 (Publication Type: Journal Article)

Chemical References

• Hypoxia-Inducible Factor 1
• Neoplasm Proteins
• Pyruvate Kinase

Topics

• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Glycolysis
• Herpesvirus 8, Human (metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypoxia-Inducible Factor 1 (metabolism)
• Neoplasm Proteins (metabolism)
• Neovascularization, Pathologic (metabolism, pathology)
• Pyruvate Kinase (biosynthesis)
• Sarcoma, Kaposi (metabolism, pathology)
• Up-Regulation