Cathepsin S Evokes PAR 2 -Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models

• Published in: Cancers Vol. 13; no. 18
• Main Authors: Tu, Nguyen Huu, Inoue, Kenji, Chen, Elyssa, Anderson, Bethany M, Sawicki, Caroline M, Scheff, Nicole N, Tran, Hung D, Kim, Dong H, Alemu, Robel G, Yang, Lei, Dolan, John C, Liu, Cheng Z, Janal, Malvin N, Latorre, Rocco, Jensen, Dane D, Bunnett, Nigel W, Edgington-Mitchell, Laura E, Schmidt, Brian L
• Format: Journal Article
• Language: English
• Published: Switzerland 19.09.2021
• Subjects: cancer pain; pain; PAR2; cathepsin S; oral squamous cell carcinoma; oral cancer; protease-activated receptor-2
• ISSN: 2072-6694; 2072-6694

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR ) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR . We report here a role for cathepsin S in PAR -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 immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate 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 PAR in Na 1.8-positive neurons (Par Na 1.8), 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 ( ) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, 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 PAR on neurons.