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PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR

Yuhong Jiang1, Junxian Lim1, Kai-Chen Wu1

  • 1Centre for Inflammation and Disease Research and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

British Journal of Pharmacology
|November 23, 2020
PubMed
Abstract

Insights

Protease-activated receptor 2 (PAR2) drives ovarian cancer cell migration and invasion through a novel cooperative signaling pathway involving multiple G proteins and beta-arrestins. This finding offers new therapeutic targets for high-grade serous ovarian cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • G protein-coupled receptors (GPCRs) mediate cellular functions through specific G protein or β-arrestin signaling.
  • Protease-activated receptor 2 (PAR2) is a GPCR implicated in various cellular processes.
  • The specific signaling mechanisms of PAR2 in ovarian cancer remain to be fully elucidated.

Purpose of the Study:

  • To investigate the role and signaling mechanisms of PAR2 in high-grade serous ovarian cancer.
  • To determine the downstream signaling pathways activated by PAR2 in ovarian cancer cells.
  • To assess the potential of targeting PAR2 for therapeutic intervention in ovarian cancer.

Main Methods:

  • Assessed PAR2 expression in human ovarian cancer tissues and cell lines.
  • Utilized cellular assays, western blots, and CRISPR-Cas9 gene knockouts in OV90 ovarian cancer cells.
  • Employed pharmacological inhibitors for PAR2 and downstream signaling proteins.

Main Results:

  • PAR2 was significantly overexpressed in ovarian cancer tissues and cell lines.
  • PAR2 activation by agonists induced ovarian cancer cell migration and invasion.
  • Signaling involved a novel cooperative activation of Gαq/11, Gα12/13, and β-arrestin1/2, leading to downstream Src, EGFR, and MEK-ERK signaling cascades.

Conclusions:

  • PAR2-induced ovarian cancer cell migration and invasion require a shared signaling cascade involving Gαq/11, Gα12/13, and β-arrestin1/2.
  • This cooperative signaling mechanism is distinct from typical individual G protein or β-arrestin pathways.
  • Targeting PAR2 or its downstream effectors presents a potential therapeutic strategy for ovarian cancer.
Keywords:
EGFRGPCRmigrationovarian cancerprotease-activated receptor 2transactivation

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