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Theileria induces oxidative stress and HIF1α activation that are essential for host leukocyte transformation

Oncogene volume 33, pages 1809–1817 (2014)Cite this article

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Abstract

Complex links between infection and cancer suggest that we still can learn much about tumorigenesis by studying how infectious agents hijack the host cell machinery. We studied the effects of an intracellular parasite called Theileria that infects bovine leukocytes and turns them into invasive cancer-like cells. We investigated the host cells pathways that are deregulated in infected leukocytes and might link infection and lymphoproliferative disease. We show that intracellular Theileria parasites drive a Warburg-like phenotype in infected host leukocytes, characterized by increased expression of metabolic regulators, increased glucose uptake and elevated lactate production, which were lost when the parasite was eliminated. The cohabitation of the parasites within the host cells leads to disruption of the redox balance (as measured by reduced/oxidized glutathione ratio) and elevated ROS (reactive oxygen species) levels, associated with chronic stabilization of the hypoxia-inducible factor 1 alpha (HIF1α). Inhibition of HIF1α (pharmacologically or genetically), or treatment with antioxidants, led to a marked reduction in expression of aerobic glycolytic genes and inhibited the transformed phenotype. These data show that stabilization of HIF1α, following increased ROS production, modulates host glucose metabolism and is critical for parasite-induced transformation. Our study expands knowledge about the molecular strategy used by the parasite Theileria to induce the transformed phenotypes of infected cells via reprogramming of glucose metabolism and redox signaling.

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Acknowledgements

We thank Slimane Ait-Si-Ali and Pierre-Antoine Defossez for critical reading of the manuscript and members of the UMR 7216 for helpful discussions. We thank Gordon Langsley for the generous gift of reagents, the Theileria-infected cell lines, the AP1-Luciferase reporter and for helpful discussions about our work. We thank Peter Staller (Biotech Research & Innovation Center, Denmark) for kindly providing the 5xHRE-luciferase constructs and Sebastien Jauliac for providing the NF-κB-Luciferase reporter. We also thank the Bioprofiler facility (Université Paris Diderot) for HPLC analysis. We thank Ayad Eddaoudi (Institute of Child Health, London, UK) for expert technical support in flow cytometry analysis. This work was supported by grants from the Association pour la Recherche contre le Cancer (ARC no. 4975 and 7990) (JBW), the Association for International Cancer Research (AICR, no. 08-0111) (JBW) and appel d'offre ‘Actions Spécifiques 2012’ Université Paris Diderot. All infected bovine cell lines used in this study have been previously characterized and published.

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  1. University Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Paris, France

    S Medjkane, M Perichon, J Marsolier & J B Weitzman

  2. University Paris Diderot, Sorbonne Paris Cité, Laboratoire de Biologie Fonctionnelle et adaptative (Equipe: RMCX), Paris, France

    J Dairou

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  1. S Medjkane
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Correspondence to J B Weitzman.

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Medjkane, S., Perichon, M., Marsolier, J. et al. Theileria induces oxidative stress and HIF1α activation that are essential for host leukocyte transformation. Oncogene 33, 1809–1817 (2014). https://doi.org/10.1038/onc.2013.134

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