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

  • Research article
  • Published:
Journal of Cell Communication and Signaling

Abstract

Drug resistance represents a major problem in cancer treatment. Doxorubicin (adriamycin) is an injectable DNA intercalating drug that halts cancer cell growth by inhibiting topoisomerase 2, but its long-term effectiveness is compromised by onset of resistance. This study demonstrates that expression of the PAR2 gene in human colon adenocarcinoma tissue samples was the highest among 32 different cancer types (n = 10,989), and higher in colon adenocarcinoma tissues (n = 331) than normal colon tissues (n = 308), revealing an association between PAR2 expression and human colon cancer. HT29 cells are a human colorectal adenocarcinoma cell line that is sensitive to the chemotherapeutic drug doxorubicin and also expresses PAR2. We find that PAR2 activation in HT29 cells, either by an endogenous protease agonist (trypsin) or an exogenous peptide agonist (2f-LIGRL-NH2), significantly reduces doxorubicin-induced cell death, reactive oxygen species production, caspase 3/7 activity and cleavage of caspase-8 and caspase-3. Moreover, PAR2-mediated MEK1/2-ERK1/2 pathway induced by 2f-LIGRL-NH2 leads to upregulated anti-apoptotic MCL-1 and Bcl-xL proteins that promote cellular survival. These findings suggest that activation of PAR2 compromises efficacy of doxorubicin in colon cancer. Further support for this conclusion came from experiments with human colon cancer HT29 cells, either with the PAR2 gene deleted or in the presence of a pharmacological antagonist of PAR2, which showed full restoration of all doxorubicin-mediated effects. Together, these findings reveal a strong link between PAR2 activation and signalling in human colon cancer cells and increased survival against doxorubicin-induced cell death. They support PAR2 antagonism as a possible new strategy for enhancing doxorubicin therapy.

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Data availability

Data that support the findings of this study are openly available in The Cancer Genome Atlas (TCGA) Pan-Cancer and The Genotype-Tissue Expression (GTEx) databases.

Abbreviations

Bcl-xL:

B-cell lymphoma-extra-large

BIM:

Bcl-2 interacting mediator of cell death

cAMP:

Cyclic adenosine monophosphate

DMSO:

Dimethyl sulfoxide

GPCR:

G protein-coupled receptor

ERK:

Extracellular signal-regulated kinases

FBS:

Fetal bovine serum

GTEx:

Genotype-Tissue Expression

MAPK:

Mitogen-activated protein kinase

MCL-1:

1-Myeloid cell leukemia-1

MTT:

(3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide)

PAR:

Protease-activated receptor

RLU:

Relative light unit

ROS:

Reactive oxygen species

TCGA:

The Cancer Genome Atlas

TL:

Tethered ligand

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Acknowledgements

Microscopy was performed at the Australian Cancer Research Foundation/Institute for Molecular Bioscience Cancer Biology Imaging Facility and Cancer Ultrastructure and Function Facility.

Funding

We thank the National Health and Medical Research Council for an Investigator Leadership L3 Award (2009551), and Australian Research Council Centre of Excellence (CE200100012) for funding different aspects of this work.

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Authors and Affiliations

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

    Himani Shah, Timothy A. Hill, Junxian Lim & David P. Fairlie

  2. Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia

    Himani Shah, Timothy A. Hill, Junxian Lim & David P. Fairlie

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  1. Himani Shah
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Contributions

JL conceived the study, HS performed all cellular studies, TAH synthesized and characterised compounds, HS, JL and DPF analysed the results and wrote the manuscript. JL and DPF led the study and obtained funding. All authors contributed to editing the final manuscript.

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Correspondence to Junxian Lim or David P. Fairlie.

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Shah, H., Hill, T.A., Lim, J. et al. Protease-activated receptor 2 attenuates doxorubicin-induced apoptosis in colon cancer cells. J. Cell Commun. Signal. 17, 1293–1307 (2023). https://doi.org/10.1007/s12079-023-00791-6

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