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

  • Research article
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Journal of Cell Communication and Signaling Aims and scope

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

References

  • Adams MN, Ramachandran R, Yau MK, Suen JY, Fairlie DP, Hollenberg MD, Hooper JD (2011) Structure, function and pathophysiology of protease activated receptors. Pharmacol Ther 130:248–282

    CAS  PubMed  Google Scholar 

  • Aoyagi T, Terracina KP, Raza A, Takabe K (2014) Current treatment options for colon cancer peritoneal carcinomatosis. World J Gastroenterol 20:12493–12500

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arakaki AK, Pan WA, Trejo J (2018) GPCRs in cancer: protease-activated receptors, endocytic adaptors and signaling. Int J Mol Sci 19(7):1886

    PubMed  PubMed Central  Google Scholar 

  • Babichev Y, Kabaroff L, Datti A, Uehling D, Isaac M, Al-Awar R, Prakesch M, Sun RX, Boutros PC, Venier R, Dickson BC, Gladdy RA (2016) PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma. J Trans Med 14:67

    Google Scholar 

  • Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F (2011) Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med 17:1490–1497

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berg KCG, Eide PW, Eilertsen IA, Johannessen B, Bruun J, Danielsen SA, Bjornslett M, Meza-Zepeda LA, Eknaes M, Lind GE, Myklebost O, Skotheim RI, Sveen A, Lothe RA (2017) Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies. Mol Cancer 16:116

    PubMed  PubMed Central  Google Scholar 

  • Booy EP, Henson ES, Gibson SB (2011) Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene 30:2367–2378

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J, Rivard N (2000) MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 79:355–369

    CAS  PubMed  Google Scholar 

  • Cao Z, Liao Q, Su M, Huang K, Jin J, Cao D (2019) AKT and ERK dual inhibitors: the way forward? Cancer Lett 459:30–40

    CAS  PubMed  Google Scholar 

  • Caruso R, Pallone F, Fina D, Gioia V, Peluso I, Caprioli F, Stolfi C, Perfetti A, Spagnoli LG, Palmieri G, Macdonald TT, Monteleone G (2006) Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation. Am J Pathol 169:268–278

    CAS  PubMed  PubMed Central  Google Scholar 

  • Caunt CJ, Sale MJ, Smith PD, Cook SJ (2015) MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 15:577–592

    CAS  PubMed  Google Scholar 

  • Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Dore AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundstrom L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N (2017) Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545:112–115

    CAS  PubMed  Google Scholar 

  • Christowitz C, Davis T, Isaacs A, van Niekerk G, Hattingh S, Engelbrecht AM (2019) Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer 19:757

    PubMed  PubMed Central  Google Scholar 

  • Consortium GT (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45:580–585

    Google Scholar 

  • Darmoul D, Gratio V, Devaud H, Laburthe M (2004) Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation. J Biol Chem 279:20927–20934

    CAS  PubMed  Google Scholar 

  • Darmoul D, Marie JC, Devaud H, Gratio V, Laburthe M (2001) Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2. Br J Cancer 85:772–779

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dhanyamraju PK, Schell TD, Amin S, Robertson GP (2022) Drug-tolerant persister cells in cancer therapy resistance. Cancer Res 82:2503–2514

    CAS  PubMed  PubMed Central  Google Scholar 

  • Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B (2012) The molecular evolution of acquired resistance to targeted egfr blockade in colorectal cancers. Nature 486:537–540

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ducroc R, Bontemps C, Marazova K, Devaud H, Darmoul D, Laburthe M (2002) Trypsin is produced by and activates protease-activated receptor-2 in human cancer colon cells: evidence for new autocrine loop. Life Sci 70:1359–1367

    CAS  PubMed  Google Scholar 

  • Dutra-Oliveira A, Monteiro RQ, Mariano-Oliveira A (2012) Protease-activated receptor-2 (PAR2) mediates VEGF production through the ERK1/2 pathway in human glioblastoma cell lines. Biochem Biophys Res Commun 421:221–227

    CAS  PubMed  Google Scholar 

  • Fang XJ, Jiang H, Zhu YQ, Zhang LY, Fan QH, Tian Y (2014) Doxorubicin induces drug resistance and expression of the novel CD44st via NF-kappaB in human breast cancer MCF-7 cells. Oncol Rep 31:2735–2742

    CAS  PubMed  Google Scholar 

  • Fernando EH, Gordon MH, Beck PL, MacNaughton WK (2018) Inhibition of intestinal epithelial wound healing through protease-activated receptor-2 activation in Caco2 cells. J Pharmacol Exp Ther 367:382–392

    CAS  PubMed  Google Scholar 

  • Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741

    CAS  PubMed  Google Scholar 

  • Goldman MJ, Craft B, Hastie M, Repecka K, McDade F, Kamath A, Banerjee A, Luo Y, Rogers D, Brooks AN, Zhu J, Haussler D (2020) Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 38:675–678

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gores GJ, Kaufmann SH (2012) Selectively targeting Mcl-1 for the treatment of acute myelogenous Leukemia and solid tumors. Genes Dev 26:305–311

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hammond WA, Swaika A, Mody K (2016) Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol 8:57–84

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heuberger DM, Schuepbach RA (2019) Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb J 17:4

    PubMed  PubMed Central  Google Scholar 

  • Iablokov V, Hirota CL, Peplowski MA, Ramachandran R, Mihara K, Hollenberg MD, MacNaughton WK (2014) Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. J Biol Chem 289:34366–34377

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP (2021a) PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR. Br J Pharmacol 178:913–932

    CAS  PubMed  Google Scholar 

  • Jiang Y, Yau MK, Kok WM, Lim J, Wu KC, Liu L, Hill TA, Suen JY, Fairlie DP (2017) Biased signaling by agonists of protease activated receptor 2. ACS Chem Biol 12:1217–1226

    CAS  PubMed  Google Scholar 

  • Jiang Y, Yau MK, Lim J, Wu KC, Xu W, Suen JY, Fairlie DP (2018) A potent antagonist of protease-activated receptor 2 that inhibits multiple signaling functions in human cancer cells. J Pharmacol Exp Ther 364:246–257

    CAS  PubMed  Google Scholar 

  • Jiang Y, Zhuo X, Fu X, Wu Y, Mao C (2021b) Targeting PAR2 overcomes gefitinib resistance in non-small-cell lung cancer cells through inhibition of EGFR transactivation. Front Pharmacol 12:625289

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Zhuo X, Wu Y, Fu X, Mao C (2022) PAR2 blockade reverses osimertinib resistance in non-small-cell lung cancer cells via attenuating ERK-mediated EMT and PD-L1 expression. Biochim Biophys Acta Mol Cell Res 1869:119144

    CAS  PubMed  Google Scholar 

  • Kennedy AJ, Sundstrom L, Geschwindner S, Poon EKY, Jiang Y, Chen R, Cooke R, Johnstone S, Madin A, Lim J, Liu Q, Lohman RJ, Nordqvist A, Friden-Saxin M, Yang W, Brown DG, Fairlie DP, Dekker N (2020) Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition. Commun Biol 3:782

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Kim HS, Seo YR (2019) Understanding of ROS-inducing strategy in anticancer therapy. Oxid Med Cell Longev 2019:5381692

    PubMed  PubMed Central  Google Scholar 

  • Kim KK, Turner R, Khazan N, Kodza A, Jones A, Singh RK, Moore RG (2020) Role of trypsin and protease-activated receptor-2 in ovarian cancer. PLoS ONE 15:e0232253

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leu CM, Chang C, Hu C (2000) Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene 19:1665–1675

    CAS  PubMed  Google Scholar 

  • Li Y, Huang H, Chen X, Yu N, Ye X, Chen L, Huang Z (2022b) PAR2 promotes tumor-associated angiogenesis in lung adenocarcinoma through activating EGFR pathway. Tissue Cell 79:101918

    CAS  PubMed  Google Scholar 

  • Li Q, Li Z, Luo T, Shi H (2022) Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy. Mol Biomed 3:47

    PubMed  PubMed Central  Google Scholar 

  • Li X, Lu Y, Liang K, Liu B, Fan Z (2005) Differential responses to doxorubicin-induced phosphorylation and activation of akt in human breast cancer cells. Breast Cancer Res 7:R589-597

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li W, Ma Y, He L, Li H, Chu Y, Jiang Z, Zhao X, Nie Y, Wang X, Wang H (2021) Protease-activated receptor 2 stabilizes Bcl-xL and regulates EGFR-targeted therapy response in colorectal cancer. Cancer Lett 517:14–23

    CAS  PubMed  Google Scholar 

  • Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP (2013) Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J 27:4757–4767

    CAS  PubMed  Google Scholar 

  • Lupertz R, Watjen W, Kahl R, Chovolou Y (2010) Dose- and time-dependent effects of doxorubicin on cytotoxicity, cell cycle and apoptotic cell death in human colon cancer cells. Toxicology 271:115–121

    PubMed  Google Scholar 

  • Matej R, Mandakova P, Netikova I, Pouckova P, Olejar T (2007) Proteinase-activated receptor-2 expression in breast cancer and the role of trypsin on growth and metabolism of breast cancer cell line MDA MB-231. Physiol Res 56:475–484

    CAS  PubMed  Google Scholar 

  • Morris DR, Ding Y, Ricks TK, Gullapalli A, Wolfe BL, Trejo J (2006) Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Res 66:307–314

    CAS  PubMed  Google Scholar 

  • Nieto Gutierrez A, McDonald PH (2018) GPCRs: emerging anti-cancer drug targets. Cell Signal 41:65–74

    CAS  PubMed  Google Scholar 

  • Pilco-Ferreto N, Calaf GM (2016) Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines. Int J Oncol 49:753–762

    CAS  PubMed  Google Scholar 

  • Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD (2012) Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 11:69–86

    CAS  PubMed  Google Scholar 

  • Ramsay AJ, Dong Y, Hunt ML, Linn M, Samaratunga H, Clements JA, Hooper JD (2008) Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J Biol Chem 283:12293–12304

    CAS  PubMed  Google Scholar 

  • Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy VB, Shimada SG, Sikand P, Lamotte RH, Lerner EA (2010) Cathepsin S elicits itch and signals via protease-activated receptors. J Invest Dermatol 130:1468–1470

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rolland-Fourcade C, Denadai-Souza A, Cirillo C, Lopez C, Jaramillo JO, Desormeaux C, Cenac N, Motta JP, Larauche M, Tache Y, Vanden Berghe P, Neunlist M, Coron E, Kirzin S, Portier G, Bonnet D, Alric L, Vanner S, Deraison C, Vergnolle N (2017) Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut 66:1767–1778

    CAS  PubMed  Google Scholar 

  • Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE (2021) A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers 13(9):2025

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelson T, Heckl D, Ebert BL, Root DE, Doench JG, Zhang F (2014) Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343:84–87

    CAS  PubMed  Google Scholar 

  • Shi K, Queiroz KC, Stap J, Richel DJ, Spek CA (2013) Protease-activated receptor-2 induces migration of pancreatic cancer cells in an extracellular ATP-dependent manner. J Thromb Haemost 11:1892–1902

    CAS  PubMed  Google Scholar 

  • Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A (2023) Colorectal cancer statistics, 2023. CA Cancer J Clin 73:233–254

    PubMed  Google Scholar 

  • Spartalis C, Schmidt EM, Elmasry M, Schulz GB, Kirchner T, Horst D (2019) In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer. Cancer Sci 110:2529–2539

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suen JY, Cotterell A, Lohman RJ, Lim J, Han A, Yau MK, Liu L, Cooper MA, Vesey DA, Fairlie DP (2014) Pathway-selective antagonism of proteinase activated receptor 2. Br J Pharmacol 171:4112–4124

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Li PB, Yao YF, Xiu AY, Peng Z, Bai YH, Gao YJ (2018) Proteinase-activated receptor 2 promotes tumor cell proliferation and metastasis by inducing epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma. World J Gastroenterol 24:1120–1133

    CAS  PubMed  PubMed Central  Google Scholar 

  • Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591

    CAS  PubMed  Google Scholar 

  • Tsai CC, Chou YT, Fu HW (2019) Protease-activated receptor 2 induces migration and promotes slug-mediated epithelial-mesenchymal transition in lung adenocarcinoma cells. Biochim Biophys Acta Mol Cell Res 1866:486–503

    CAS  PubMed  Google Scholar 

  • Ungefroren H, Witte D, Rauch BH, Settmacher U, Lehnert H, Gieseler F, Kaufmann R (2017) Proteinase-activated receptor 2 may drive cancer progression by facilitating TGF-β signaling. Int J Mol Sci 18(11):2494

    PubMed  PubMed Central  Google Scholar 

  • Van Opdenbosch N, Lamkanfi M (2019) Caspases in cell death, inflammation, and disease. Immunity 50:1352–1364

    PubMed  PubMed Central  Google Scholar 

  • Versteeg HH, Schaffner F, Kerver M, Ellies LG, Andrade-Gordon P, Mueller BM, Ruf W (2008) Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice. Cancer Res 68:7219–7227

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Stuart JM (2013) The cancer genome atlas pan-cancer analysis project. Nat Genet 45(10):1113–1120

    PubMed  PubMed Central  Google Scholar 

  • Wickenden JA, Jin H, Johnson M, Gillings AS, Newson C, Austin M, Chell SD, Balmanno K, Pritchard CA, Cook SJ (2008) Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM. Oncogene 27:7150–7161

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, Hawthorne S (2005) The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochem J 388:967–972

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu V, Yeerna H, Nohata N, Chiou J, Harismendy O, Raimondi F, Inoue A, Russell RB, Tamayo P, Gutkind JS (2019) Illuminating the Onco-GPCRome: novel G protein-coupled receptor-driven oncocrine networks and targets for cancer immunotherapy. J Biol Chem 294:11062–11086

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong S, Xiao GW (2018) Reverting doxorubicin resistance in colon cancer by targeting a key signaling protein, steroid receptor coactivator. Exp Ther Med 15:3751–3758

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang MC, Lin RW, Huang SB, Huang SY, Chen WJ, Wang S, Hong YR, Wang C (2016) Bim directly antagonizes bcl-xl in doxorubicin-induced prostate cancer cell apoptosis independently of p53. Cell Cycle 15:394–402

    CAS  PubMed  Google Scholar 

  • Yu HG, Ai YW, Yu LL, Zhou XD, Liu J, Li JH, Xu XM, Liu S, Chen J, Liu F, Qi YL, Deng Q, Cao J, Liu SQ, Luo HS, Yu JP (2008) Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer 122:433–443

    CAS  PubMed  Google Scholar 

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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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  2. Timothy A. Hill
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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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