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Extracellular ATP Induced S-Phase Cell Cycle Arrest via P2Y Receptor-Activated ERK Signaling in Poorly Differentiated

Chia Chih Lau1, Amnani Aminuddin1, Kok Meng Chan2

  • 1Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia.

Life (Basel, Switzerland)
|November 27, 2021
PubMed

Insights

Extracellular ATP shows potential antitumor effects in oral squamous cell carcinoma (OSCC) by inducing cell cycle arrest via P2Y receptor-mediated ERK signaling. This highlights ATP

Area of Science:

  • Molecular Oncology
  • Cancer Signaling Pathways

Background:

  • Extracellular ATP's role in the tumor microenvironment is complex, with potential pro- or antitumor effects mediated by P2Y receptors.
  • The specific intracellular signaling and functional roles of P2Y receptors in oral squamous cell carcinoma (OSCC) remain largely uncharacterized.

Purpose of the Study:

  • To investigate the effects of extracellular ATP on OSCC cell lines.
  • To elucidate the potential intracellular signaling mechanisms involved in ATP's action on OSCC.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) data via GEPIA for P2Y receptor mRNA expression and patient survival correlation.
  • Quantitative PCR (qPCR) to assess P2RY1 expression in different OSCC cell lines (SAS, H103, H376).
  • Western blotting and flow cytometry to evaluate ATP-induced extracellular signal-regulated kinase (ERK) phosphorylation and intracellular calcium levels.
  • Cell cycle analysis and apoptosis assays in response to ATP and MEK inhibitor (PD0325901).

Main Results:

  • High mRNA expression of P2Y receptors correlated with better overall survival in head and neck squamous cell carcinoma patients.
  • The poorly differentiated OSCC SAS cell line exhibited higher P2RY1 expression compared to well-differentiated cell lines.
  • ATP induced ERK phosphorylation and elevated intracellular calcium in all tested OSCC cell lines.
  • ATP caused significant S-phase cell cycle arrest in SAS cells, which was reversed by MEK inhibition.
  • ATP treatment led to reduced cell count, colony formation, and induced apoptosis in SAS cells.

Conclusions:

  • Extracellular ATP, acting through P2Y receptors, can induce S-phase cell cycle arrest in OSCC SAS cells, potentially via ERK signaling.
  • These findings suggest a potential antitumor role for extracellular ATP in oral squamous cell carcinoma, warranting further investigation.
Keywords:
ERK signalingP2Y receptorsS-phase arrestextracellular ATPoral squamous cell carcinoma

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