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Featured ArticleResearch Articles, Neurobiology of Disease

Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2

Nguyen Huu Tu, Dane D. Jensen, Bethany M. Anderson, Elyssa Chen, Nestor N. Jimenez-Vargas, Nicole N. Scheff, Kenji Inoue, Hung D. Tran, John C. Dolan, Tamaryn A. Meek, Morley D. Hollenberg, Cheng Z. Liu, Stephen J. Vanner, Malvin N. Janal, Nigel W. Bunnett, Laura E. Edgington-Mitchell and Brian L. Schmidt
Journal of Neuroscience 6 January 2021, 41 (1) 193-210; DOI: https://doi.org/10.1523/JNEUROSCI.1211-20.2020
Nguyen Huu Tu
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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Dane D. Jensen
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
2Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010
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Bethany M. Anderson
3Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC 3010
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  • ORCID record for Bethany M. Anderson
Elyssa Chen
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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Nestor N. Jimenez-Vargas
4Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, ON K7L 3N6, Canada
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Nicole N. Scheff
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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Kenji Inoue
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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Hung D. Tran
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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John C. Dolan
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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Tamaryn A. Meek
5Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052
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Morley D. Hollenberg
6Inflammation Research Network-Snyder Institute for Chronic Disease, Physiology and Pharmacology Department, and Medicine Department, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
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Cheng Z. Liu
7Department of Pathology, New York University Langone Health, New York, NY 10016
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Stephen J. Vanner
4Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, ON K7L 3N6, Canada
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Malvin N. Janal
8Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY 10010
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Nigel W. Bunnett
2Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010
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Laura E. Edgington-Mitchell
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
3Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC 3010
5Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052
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Brian L. Schmidt
1Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010
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Abstract

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2 in NaV1.8-positive neurons (Par2Nav1.8), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par2Nav1.8 and Lgmn deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons from WT female mice. Par2 deletion, LI-1, and inhibitors of adenylyl cyclase or protein kinase A (PKA) prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N terminus of PAR2 at Asn30↓Arg31, proximal to the canonical trypsin activation site. Lgmn activated PAR2 by biased mechanisms in HEK293 cells to induce Ca2+ mobilization, cAMP formation, and PKA/protein kinase D (PKD) activation, but not β-arrestin recruitment or PAR2 endocytosis. Thus, in the acidified OSCC microenvironment, Lgmn activates PAR2 by biased mechanisms that evoke cancer pain.

SIGNIFICANCE STATEMENT Oral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR2) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared with matched normal oral tissue. Lgmn evokes pain-like behavior through PAR2. Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR2. Inhibitors of adenylyl cyclase and protein kinase A (PKA) prevented the effects of Lgmn. Lgmn activated PAR2 to induce calcium mobilization, cAMP formation, and activation of protein kinase D (PKD) and PKA, but not β-arrestin recruitment or PAR2 endocytosis. Thus, Lgmn is a biased agonist of PAR2 that evokes cancer pain.

  • asparaginyl endopeptidase
  • cancer pain
  • legumain
  • oral cancer
  • protease
  • protease-activated receptor-2

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The Journal of Neuroscience: 41 (1)
Journal of Neuroscience
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6 Jan 2021
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Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2
Nguyen Huu Tu, Dane D. Jensen, Bethany M. Anderson, Elyssa Chen, Nestor N. Jimenez-Vargas, Nicole N. Scheff, Kenji Inoue, Hung D. Tran, John C. Dolan, Tamaryn A. Meek, Morley D. Hollenberg, Cheng Z. Liu, Stephen J. Vanner, Malvin N. Janal, Nigel W. Bunnett, Laura E. Edgington-Mitchell, Brian L. Schmidt
Journal of Neuroscience 6 January 2021, 41 (1) 193-210; DOI: 10.1523/JNEUROSCI.1211-20.2020

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Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2
Nguyen Huu Tu, Dane D. Jensen, Bethany M. Anderson, Elyssa Chen, Nestor N. Jimenez-Vargas, Nicole N. Scheff, Kenji Inoue, Hung D. Tran, John C. Dolan, Tamaryn A. Meek, Morley D. Hollenberg, Cheng Z. Liu, Stephen J. Vanner, Malvin N. Janal, Nigel W. Bunnett, Laura E. Edgington-Mitchell, Brian L. Schmidt
Journal of Neuroscience 6 January 2021, 41 (1) 193-210; DOI: 10.1523/JNEUROSCI.1211-20.2020
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Keywords

  • asparaginyl endopeptidase
  • cancer pain
  • legumain
  • oral cancer
  • protease
  • protease-activated receptor-2

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