Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models
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<sub>2</sub>) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injur...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/18/4697 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nguyen Huu Tu |
| collection | DOAJ |
| description | 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<sub>2</sub>) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR<sub>2</sub>. We report here a role for cathepsin S in PAR<sub>2</sub>-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<sub>2</sub> in Na<sub>v</sub>1.8-positive neurons (Par<sub>2</sub>Na<sub>v</sub>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 (<i>CTSS</i>) 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<sub>2</sub> on neurons. |
| first_indexed | 2024-03-10T07:50:13Z |
| format | Article |
| id | doaj.art-4c525d8763034d1d8c4b522aa21ceb21 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T07:50:13Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4c525d8763034d1d8c4b522aa21ceb212023-11-22T12:19:12ZengMDPI AGCancers2072-66942021-09-011318469710.3390/cancers13184697Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse ModelsNguyen Huu Tu0Kenji Inoue1Elyssa Chen2Bethany M. Anderson3Caroline M. Sawicki4Nicole N. Scheff5Hung D. Tran6Dong H. Kim7Robel G. Alemu8Lei Yang9John C. Dolan10Cheng Z. Liu11Malvin N. Janal12Rocco Latorre13Dane D. Jensen14Nigel W. Bunnett15Laura E. Edgington-Mitchell16Brian L. Schmidt17Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USADepartment of Biochemistry and Pharmacology, Bio21 Institute, University of Melbourne, Parkville, VIC 3052, AustraliaBluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USAPathology Department, New York University (NYU) Langone Health, New York, NY 10016, USADepartment of Epidemiology and Health Promotion, New York University (NYU) College of Dentistry, New York, NY 10010, USADepartment of Molecular Pathobiology, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USADepartment of Molecular Pathobiology, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USABluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University (NYU) College of Dentistry, New York, NY 10010, USAOral 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<sub>2</sub>) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR<sub>2</sub>. We report here a role for cathepsin S in PAR<sub>2</sub>-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<sub>2</sub> in Na<sub>v</sub>1.8-positive neurons (Par<sub>2</sub>Na<sub>v</sub>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 (<i>CTSS</i>) 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<sub>2</sub> on neurons.https://www.mdpi.com/2072-6694/13/18/4697oral cancerpaincathepsin Sprotease-activated receptor-2PAR<sub>2</sub>cancer pain |
| spellingShingle | 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 Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models Cancers oral cancer pain cathepsin S protease-activated receptor-2 PAR<sub>2</sub> cancer pain |
| title | Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models |
| title_full | Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models |
| title_fullStr | Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models |
| title_full_unstemmed | Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models |
| title_short | Cathepsin S Evokes PAR<sub>2</sub>-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models |
| title_sort | cathepsin s evokes par sub 2 sub dependent pain in oral squamous cell carcinoma patients and preclinical mouse models |
| topic | oral cancer pain cathepsin S protease-activated receptor-2 PAR<sub>2</sub> cancer pain |
| url | https://www.mdpi.com/2072-6694/13/18/4697 |
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