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Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts
Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have app...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386754/ https://www.ncbi.nlm.nih.gov/pubmed/30796200 http://dx.doi.org/10.1038/s41389-019-0121-7 |
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author | Chen, Chun-Hau Bhasin, Swati Khanna, Prateek Joshi, Mukta Joslin, Patrick MN. Saxena, Ruchi Amin, Seema Liu, Suhu Sindhu, Shreya Walker, Sarah R. Catalano, Paul Frank, David A. Alper, Seth L. Bhasin, Manoj Bhatt, Rupal S. |
author_facet | Chen, Chun-Hau Bhasin, Swati Khanna, Prateek Joshi, Mukta Joslin, Patrick MN. Saxena, Ruchi Amin, Seema Liu, Suhu Sindhu, Shreya Walker, Sarah R. Catalano, Paul Frank, David A. Alper, Seth L. Bhasin, Manoj Bhatt, Rupal S. |
author_sort | Chen, Chun-Hau |
collection | PubMed |
description | Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have applied integrated transcriptome and proteome analyses to identify cathepsin B (CTSB), a cysteine proteinase of the papain family, as one of the most highly upregulated gene products in established human RCC xenograft models of resistance to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). We used established RCC models to test the significance of CTSB in the progression of renal cancer. Our evaluation of CTSB showed that stable CTSB knockdown suppressed RCC growth in vitro and in vivo. Stable over-overexpression of wild-type CTSB (CTSB(wt/hi)), but not of an CTSB active site mutant (CTSB(N298A)), rescued cell growth in CTSB knockdown cells and abolished the efficacy of VEGFR TKI treatment. Genome-wide transcriptome profiling of CTSB knockdown cells demonstrated significant effects on multiple metabolic and stem cell-related pathways, with ALDHA1A (ALDH1) as one of the most significantly downregulated genes. Importantly, survival analysis across 16 major TCGA cancers revealed that CTSB overexpression is associated with low rates of three and five year patient survival rates (P = 2.5e–08, HR = 1.4). These data strongly support a contribution of CTSB activity to RCC cell growth and tumorigenicity. They further highlight the promise of CTSB inhibition in development of novel combination therapies designed to improve efficacy of current TKI treatments of metastatic RCC. |
format | Online Article Text |
id | pubmed-6386754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63867542019-02-25 Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts Chen, Chun-Hau Bhasin, Swati Khanna, Prateek Joshi, Mukta Joslin, Patrick MN. Saxena, Ruchi Amin, Seema Liu, Suhu Sindhu, Shreya Walker, Sarah R. Catalano, Paul Frank, David A. Alper, Seth L. Bhasin, Manoj Bhatt, Rupal S. Oncogenesis Article Several therapeutic options are available for metastatic RCC, but responses are almost never complete, and resistance to therapy develops in the vast majority of patients. Consequently, novel treatments are needed to combat resistance to current therapies and to improve patient outcomes. We have applied integrated transcriptome and proteome analyses to identify cathepsin B (CTSB), a cysteine proteinase of the papain family, as one of the most highly upregulated gene products in established human RCC xenograft models of resistance to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). We used established RCC models to test the significance of CTSB in the progression of renal cancer. Our evaluation of CTSB showed that stable CTSB knockdown suppressed RCC growth in vitro and in vivo. Stable over-overexpression of wild-type CTSB (CTSB(wt/hi)), but not of an CTSB active site mutant (CTSB(N298A)), rescued cell growth in CTSB knockdown cells and abolished the efficacy of VEGFR TKI treatment. Genome-wide transcriptome profiling of CTSB knockdown cells demonstrated significant effects on multiple metabolic and stem cell-related pathways, with ALDHA1A (ALDH1) as one of the most significantly downregulated genes. Importantly, survival analysis across 16 major TCGA cancers revealed that CTSB overexpression is associated with low rates of three and five year patient survival rates (P = 2.5e–08, HR = 1.4). These data strongly support a contribution of CTSB activity to RCC cell growth and tumorigenicity. They further highlight the promise of CTSB inhibition in development of novel combination therapies designed to improve efficacy of current TKI treatments of metastatic RCC. Nature Publishing Group UK 2019-02-22 /pmc/articles/PMC6386754/ /pubmed/30796200 http://dx.doi.org/10.1038/s41389-019-0121-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Chen, Chun-Hau Bhasin, Swati Khanna, Prateek Joshi, Mukta Joslin, Patrick MN. Saxena, Ruchi Amin, Seema Liu, Suhu Sindhu, Shreya Walker, Sarah R. Catalano, Paul Frank, David A. Alper, Seth L. Bhasin, Manoj Bhatt, Rupal S. Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts |
title | Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts |
title_full | Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts |
title_fullStr | Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts |
title_full_unstemmed | Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts |
title_short | Study of Cathepsin B inhibition in VEGFR TKI treated human renal cell carcinoma xenografts |
title_sort | study of cathepsin b inhibition in vegfr tki treated human renal cell carcinoma xenografts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386754/ https://www.ncbi.nlm.nih.gov/pubmed/30796200 http://dx.doi.org/10.1038/s41389-019-0121-7 |
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