Research Papers:

Stimulation of the toll-like receptor 3 promotes metabolic reprogramming in head and neck carcinoma cells

Mathieu Veyrat, Sylvère Durand, Marion Classe, Tanja Matijevic Glavan, Natalie Oker, Nikiforos-Ioannis Kapetanakis, Xiaojun Jiang, Aurore Gelin, Philippe Herman, Odile Casiraghi, David Zagzag, David Enot, Pierre Busson and Benjamin Vérillaud _

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Oncotarget. 2016; 7:82580-82593. https://doi.org/10.18632/oncotarget.12892

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Mathieu Veyrat1, Sylvère Durand2, Marion Classe3, Tanja Matijevic Glavan4, Natalie Oker1,5, Nikiforos-Ioannis Kapetanakis1, Xiaojun Jiang1, Aurore Gelin1, Philippe Herman5, Odile Casiraghi6, David Zagzag7, David Enot2, Pierre Busson1, Benjamin Vérillaud1,5

1University Paris-Sud (Paris 11), CNRS-UMR 8126, Gustave Roussy, Villejuif, France

2Equipe 11 Labélisée par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France, Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif, France

3Department of Pathology, Lariboisière Hospital, AP-HP, University Paris-Diderot Paris 7, Paris, France

4Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia

5Department of Head and Neck surgery, Lariboisière Hospital, AP-HP, University Paris-Diderot Paris 7, Paris, France

6Department of Biopathology, Gustave Roussy, Villejuif, France

7Department of Neuropathology, New York University School of Medicine, New York, NY, USA

Correspondence to:

Benjamin Vérillaud, email: [email protected]

Keywords: toll-like receptor 3, innate immunity, warburg effect, HIF, metabolomics

Received: February 12, 2015     Accepted: October 19, 2016     Published: October 25, 2016


In this study, a possible link between the innate immune recognition receptor TLR3 and metabolic reprogramming in Head and Neck carcinoma (HNC) cells was investigated. The effects of TLR3 stimulation/knock-down were assessed under several culture conditions in 4 HNC cell-lines by cell growth assays, targeted metabolomics, and glycolysis assays based on time-resolved analysis of proton release (Seahorse analyzer). The stimulation of TLR3 by its synthetic agonist Poly(A:U) resulted in a faster growth of HNC cells under low foetal calf serum conditions. Targeted analysis of glucose metabolism pathways demonstrated a tendency towards a shift from tricarboxylic acid cycle (Krebs cycle) to glycolysis and anabolic reactions in cells treated with Poly(A:U). Glycolysis assays confirmed that TLR3 stimulation enhanced the capacity of malignant cells to switch from oxidative phosphorylation to extra-mitochondrial glycolysis. We found evidence that HIF-1α is involved in this process: addition of the TLR3 agonist resulted in a higher cell concentration of the HIF-1α protein, even in normoxia, whereas knocking-down TLR3 resulted in a lower concentration, even in hypoxia. Finally, we assessed TLR3 expression by immunohistochemistry in a series of 7 HNSCC specimens and found that TLR3 was detected at higher levels in tumors displaying a hypoxic staining pattern. Overall, our results demonstrate that TLR3 stimulation induces the Warburg effect in HNC cells in vitro, and suggest that TLR3 may play a role in tumor adaptation to hypoxia.

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