Crucial role of HSP90 in the Akt-dependent promotion of angiogenic-like effect of glucose-regulated protein94 (Grp94)-IgG complexes.
Bottom Line: CCT failed to inhibit any morphological alteration induced by Grp94-IgG on HUVECs, on its own displaying a paradoxical angiogenic-like activity.CTT appeared to enhance the angiogenic-like effect of Grp94-IgG by increasing the rate of secretion of both HSP90 and MMP-9.Results reveal a fundamental role of HSP90 in the PI3K/Akt pathway-mediated angiogenic-like effect of Grp94-IgG, also questioning the capacity of CTT to serve as an effective inhibitor of the angiogenic effect.
Affiliation: Department of Pharmacology and Anesthesiology, University of Padova, Largo E. Meneghetti, Padova, Italy.Show MeSH
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Mentions: We previously demonstrated that both the stimulation of endothelial cell proliferation and induction of differentiation by Grp94-IgG were mediated by an intense activation of the MEK-ERK1/2 pathway, even higher than that observed with native Grp94 alone . An intense and prolonged activation of ERK1/2 is recognized to underlie the differentiation of HUVECs into tubule-like formations [17, 18]. Because CTT on its own was apparently as active as Grp94-IgG in inducing the differentiation process of endothelial cells, it was of interest to see whether MEK-ERK1/2 pathway was further stimulated by the addition of CTT. After 18 hrs incubation, an intense phosphorylation of ERK1/2 was observed with Grp94-IgG (Fig. 2A), further stimulated by pre-treatment with CTT, irrespective of the concentration, a finding that supported the permissive effect of CTT on the induction of angiogenic-like transformation of HUVECs. The same result however excluded that the MEK-ERK1/2 pathway was directly involved in mediating the inhibition of cell proliferation by CTT. Because CTT alone did not affect at all the phosphorylation of ERK1/2 (the signal was even lower than that of control) (Fig. 2A), the effect of enhancement of ERK1/2 phosphorylation by CTT could be explained by invoking an indirect mechanism of activation by CTT on a pathway, also targeted by Grp94-IgG, other than the MEK-ERK1/2 one.
Affiliation: Department of Pharmacology and Anesthesiology, University of Padova, Largo E. Meneghetti, Padova, Italy.