Journal article

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



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..

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Awarded by National Institutes of Health

Awarded by Department of Defense

Awarded by Priority-Driven Collaborative Cancer Research Grant

Awarded by Australian Research Council

Funding Acknowledgements

This work was supported by National Institutes of Health Grants NS102722, DE026806, DK118971, and DE029951 (to N.W.B., B.L.S.) and the Department of Defense Grant W81XWH1810431 (to N.W.B., B.L.S.). L.E.E.-M. was supported by the Priority-Driven Collaborative Cancer Research Grant GNT1157171 (co-funded by Cancer Australia and Cure Cancer), a Grimwade Fellowship from the Russell and Mab Grimwade Miegunyah Fund at The University of Melbourne, and the Australian Research Council Discovery Early Career Researcher Award Fellowship DE180100418.