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

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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.

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Authors and Affiliations

  1. Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W. Baltimore Street, 7th North, Rm 7263, Baltimore, MD, 21201, USA

    Tao Ma, Harsh Patel, Renty Franklin & Silvia Montaner

  2. Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA

    Silvia Montaner

  3. Greenebaum Cancer Center, University of Maryland, Baltimore, MD, 21201, USA

    Renty Franklin & Silvia Montaner

  4. Wilmer Eye Institute, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, 21287, USA

    Savalan Babapoor-Farrokhran & Akrit Sodhi

  5. Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Gregg L. Semenza

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  1. Tao Ma
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Correspondence to Silvia Montaner.

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Ma, T., Patel, H., Babapoor-Farrokhran, S. et al. KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis 18, 477–488 (2015). https://doi.org/10.1007/s10456-015-9475-4

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  • DOI: https://doi.org/10.1007/s10456-015-9475-4

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