Nucleotide receptors stimulation by extracellular ATP controls Hsp90 expression through APE1/Ref-1 in thyroid cancer cells: A novel tumorigenic pathway

摘要: Nucleotide receptors signaling affects cell proliferation, with possible implications on tumorigenic processes. However, molecular targets and action mechanisms of the extracellular nucleotides are still poorly elucidated. We have previously shown in ARO cells that APE1/Ref-1, a transcriptional coactivator responsible for maintenance cellular proliferative rate, is functionally controlled by P2-mediated signaling. Here, we demonstrate ATP has mitogenic effect cells, increasing ERK phosphorylation, AP1 activation, cyclin D1 expression. Using ATP/ADPase apyrase P2 receptor antagonist suramin, show ATP, physiologically released exerts effects. A differential proteomic approach was used to identify events associated ATP-induced proliferation. Among other proteins, Hsp90 found upregulated upon stimulation. Pretreatment suramin completely blocked confirming involvement cell-surface nucleotide ATP-mediated activation cells. Treatment proliferating significantly reduced intracellular levels Hsp90, suggesting an autocrine/paracrine mechanism control expression ATP. The influence proliferation also demonstrated its specific inhibition 17-AAG. pathway which stimulates further investigated siRNA strategies showing target APE1/Ref-1 functional activation. Stimulation agonists evidenced major P2Y1 P2Y2 controlling Accordingly, these two resulted sample biopsies from different thyroid tumors. J. Cell. Physiol. 209: 44–55, 2006. © 2006 Wiley-Liss, Inc.