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Nucleotide receptors stimulation by extracellular ATP controls Hsp90 expression through APE1/Ref-1 in thyroid cancer

Alex Pines1, Nicoletta Bivi, Carlo Vascotto

  • 1Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy.

Journal of Cellular Physiology
|June 3, 2006
PubMed

Insights

Extracellular adenosine triphosphate (ATP) promotes thyroid cancer cell proliferation by activating P2Y1 and P2Y2 receptors, which upregulate heat shock protein 90 (Hsp90). This pathway involves APE1/Ref-1 and impacts cell growth.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Cancer research

Background:

  • Extracellular nucleotide signaling influences cell proliferation and tumorigenesis.
  • Molecular targets and mechanisms of extracellular nucleotides remain poorly understood.
  • Previous work implicated APE1/Ref-1 in P2-mediated signaling controlling proliferation in ARO cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which extracellular adenosine triphosphate (ATP) stimulates cell proliferation in ARO cells.
  • To identify molecular targets and signaling pathways involved in ATP-induced mitogenesis.
  • To investigate the role of heat shock protein 90 (Hsp90) and specific P2 receptors in this process.

Main Methods:

  • Utilized ARO cells and treated them with ATP, apyrase, and suramin.
  • Employed proteomic analysis to identify ATP-modulated proteins, including Hsp90.
  • Investigated signaling pathways using ERK phosphorylation, AP1 activation, cyclin D1 expression, and siRNA strategies.
  • Stimulated cells with specific P2 receptor agonists (P2Y1, P2Y2) and analyzed Hsp90 activation.
  • Examined Hsp90 levels in thyroid tumor biopsies.

Main Results:

  • Extracellular ATP demonstrated a mitogenic effect on ARO cells, increasing ERK phosphorylation, AP1 activation, and cyclin D1 expression.
  • Proteomic analysis identified Hsp90 as upregulated upon ATP stimulation, with its activation blocked by suramin.
  • Extracellular ATP, physiologically released by ARO cells, exerts mitogenic effects via an autocrine/paracrine mechanism involving Hsp90.
  • Hsp90 was identified as a target of APE1/Ref-1 functional activation.
  • P2Y1 and P2Y2 receptors were significantly involved in Hsp90 activation and were upregulated in thyroid tumors.

Conclusions:

  • Extracellular ATP promotes thyroid cancer cell proliferation through P2Y1 and P2Y2 receptor activation, leading to Hsp90 upregulation and APE1/Ref-1 functional activation.
  • Hsp90 plays a crucial role in the ATP-induced mitogenic signaling pathway.
  • The identified P2 receptor-Hsp90-APE1/Ref-1 axis represents a potential therapeutic target for thyroid tumors.

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