Cathepsin s evokes par2-dependent pain in oral squamous cell carcinoma patients and preclinical mouse models

Nguyen Huu Tu, Kenji Inoue, Elyssa Chen, Bethany M. Anderson, Caroline M. Sawicki, Nicole N. Scheff, Hung D. Tran, Dong H. Kim, Robel G. Alemu, Lei Yang, John C. Dolan, Cheng Z. Liu, Malvin N. Janal, Rocco Latorre, Dane D. Jensen, Nigel W. Bunnett, Laura E. Edgington-Mitchell, Brian L. Schmidt

Research output: Contribution to journalArticlepeer-review


Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain gener-ated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immuno-localization of cathepsin S in human oral cancers suggests that carcinoma and macrophages gener-ate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperal-gesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.

Original languageEnglish (US)
Article number4697
Issue number18
StatePublished - Sep 2021


  • Cancer pain
  • Cathepsin S
  • Oral cancer
  • Oral squamous cell carcinoma
  • PAR2
  • Pain
  • Protease-activated receptor-2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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