Journal
ONCOGENE
Volume 33, Issue 14, Pages 1809-1817Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.134
Keywords
leukocyte transformation; Warburg effect; metabolism; Theileria; host-parasite interactions
Funding
- Association pour la Recherche contre le Cancer (ARC) [4975, 7990]
- Association for International Cancer Research (AICR) [08-0111]
- appel d'offre 'Actions Specifiques Universite Paris Diderot
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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 (HIF1 alpha). Inhibition of HIF1 alpha (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 HIF1a, 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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