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Adenosine triphosphate drives head and neck cancer pain through P2X2/3 heterotrimers

Yi Ye, Kentaro Ono, Daniel G Bernabé

  • 1Bluestone Center for Clinical Research, New York University, 421 First Avenue, 233 W, New York, NY 10010, USA. bls322@nyu.edu.

Acta Neuropathologica Communications
|June 7, 2014
PubMed
Abstract

Insights

Increased adenosine triphosphate (ATP) in head and neck squamous cell carcinoma (HNSCC) correlates with pain. Targeting P2X2 and P2X3 receptors may alleviate cancer pain.

Area of Science:

  • Neuroscience
  • Oncology
  • Pain Research

Background:

  • Cancer pain significantly impacts patient quality of life and survival.
  • The underlying neurobiology of cancer pain, particularly in head and neck squamous cell carcinoma (HNSCC), remains incompletely understood.
  • Adenosine triphosphate (ATP) and its ionotropic receptor subunits P2X2 and P2X3 are implicated in cancer pain in animal models.

Purpose of the Study:

  • To investigate the role of ATP and P2X2/P2X3 receptors in human HNSCC-associated pain.
  • To determine the contribution of P2X2- and P2X3-containing trimeric channels to cancer pain.
  • To explore the influence of nerve growth factor (NGF) on these pain mechanisms.

Main Methods:

  • Analysis of ATP levels in human HNSCC tissues and matched normal tissues.
  • Immunohistochemical examination of P2X2 and P2X3 subunit expression in human HNSCC nerve fibers.
  • Utilizing animal models of HNSCC to study ATP-mediated pain via P2X2/3 receptors.
  • Investigating the effect of NGF on P2X2 and P2X3 receptor function and expression in murine trigeminal ganglion neurons.

Main Results:

  • Human HNSCC tissues exhibit significantly elevated ATP levels compared to normal tissues.
  • High ATP levels in HNSCC positively correlate with patient-reported pain intensity.
  • Nerve fibers expressing both P2X2 and P2X3 subunits are abundant in the HNSCC microenvironment.
  • ATP in the cancer microenvironment exacerbates pain perception through P2X2/3 receptors in animal models.
  • NGF induces hypersensitivity and increases expression of P2X2 and P2X3 subunits in neurons.

Conclusions:

  • A key peripheral mechanism involving ATP and P2X2/3 receptors in cancer pain is identified.
  • Targeting nociceptors expressing P2X2 and P2X3 subunits, such as P2X2/3 heterotrimers, shows clinical potential for cancer pain relief.

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