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Protease-activated receptor 2 attenuates doxorubicin-induced apoptosis in colon cancer cells

Himani Shah1,2, Timothy A Hill1,2, Junxian Lim3,4

  • 1Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.

Journal of Cell Communication and Signaling
|November 22, 2023
PubMed

Insights

Activation of the PAR2 gene in colon cancer cells reduces the effectiveness of doxorubicin chemotherapy by promoting cell survival. Blocking PAR2 may enhance doxorubicin treatment efficacy for colon cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Drug resistance, particularly to doxorubicin, is a significant challenge in cancer therapy.
  • Doxorubicin efficacy is limited by the development of resistance.
  • The role of Protease-Activated Receptor 2 (PAR2) in colon cancer and its impact on chemotherapy response is not fully understood.

Purpose of the Study:

  • To investigate the association between PAR2 expression and human colon cancer.
  • To determine the effect of PAR2 activation on doxorubicin-induced cell death in colon cancer cells.
  • To explore the potential of PAR2 antagonism as a strategy to overcome doxorubicin resistance.

Main Methods:

  • Analysis of PAR2 gene expression in human colon adenocarcinoma tissues and cell lines.
  • Activation of PAR2 in HT29 colon cancer cells using specific agonists.
  • Assessment of doxorubicin-induced cell death, apoptosis markers, and signaling pathways (MEK1/2-ERK1/2).
  • Evaluation of doxorubicin effects in HT29 cells with PAR2 gene deletion or PAR2 antagonist treatment.

Main Results:

  • PAR2 gene expression is significantly higher in colon adenocarcinoma tissues compared to normal tissues and is elevated across various cancer types.
  • PAR2 activation in HT29 cells reduces doxorubicin-induced cell death, apoptosis, and reactive oxygen species production.
  • PAR2 activation upregulates anti-apoptotic proteins MCL-1 and Bcl-xL via the MEK1/2-ERK1/2 pathway, promoting cell survival.
  • PAR2 antagonism or gene deletion restores doxorubicin sensitivity in colon cancer cells.

Conclusions:

  • PAR2 activation compromises doxorubicin efficacy in colon cancer by promoting cell survival.
  • PAR2 signaling plays a crucial role in mediating resistance to doxorubicin in colon adenocarcinoma.
  • Targeting PAR2 through antagonism presents a potential therapeutic strategy to enhance doxorubicin treatment outcomes in colon cancer.
Keywords:
ApoptosisColon cancerDoxorubicinPAR2Resistance

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