Transactivation of the epidermal growth factor receptor by heat shock protein 90 via Toll-like receptor 4 contributes to the migration of glioblastoma cells.

Fiche publication

Date publication

février 2011


Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen, Dr THURINGER Dominique

Tous les auteurs :
Thuringer D, Hammann A, Benikhlef N, Fourmaux E, Bouchot A, Wettstein G, Solary E, Garrido C


Extracellular heat shock protein HSP90alpha was reported to participate in tumor cell growth, invasion, and metastasis formation through poorly understood signaling pathways. Herein, we show that extracellular HSP90alpha favors cell migration of glioblastoma U87 cells. More specifically, externally applied HSP90alpha rapidly induced endocytosis of EGFR. This response was accompanied by a transient increase in cytosolic Ca(2+) appearing after 1-3 min of treatment. In the presence of EGF, U87 cells showed HSP90alpha-induced Ca(2+) oscillations, which were reduced by the ATP/ADPase, apyrase, and inhibited by the purinergic P(2) inhibitor, suramin, suggesting that ATP release is requested. Disruption of lipid rafts with methyl beta-cyclodextrin impaired the Ca(2+) rise induced by extracellular HSP90alpha combined with EGF. Specific inhibition of TLR4 expression by blocking antibodies suppressed extracellular HSP90alpha-induced Ca(2+) signaling and the associated cell migration. HSPs are known to bind lipopolysaccharides (LPSs). Preincubating cells with Polymyxin B, a potent LPS inhibitor, partially abrogated the effects of HSP90alpha without affecting Ca(2+) oscillations observed with EGF. Extracellular HSP90alpha induced EGFR phosphorylation at Tyr-1068, and this event was prevented by both the protein kinase Cdelta inhibitor, rottlerin, and the c-Src inhibitor, PP2. Altogether, our results suggest that extracellular HSP90alpha transactivates EGFR/ErbB1 through TLR4 and a PKCdelta/c-Src pathway, which induces ATP release and cytosolic Ca(2+) increase and finally favors cell migration. This mechanism could account for the deleterious effects of HSPs on high grade glioma when released into the tumor cell microenvironment.


J Biol Chem. 2011 Feb 4;286(5):3418-28