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Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

  • Anthony J. O’Donoghue EMAIL logo , Sam L. Ivry , Chaity Chaudhury , Daniel R. Hostetter , Douglas Hanahan and Charles S. Craik EMAIL logo
Published/Copyright: May 4, 2016
Biological Chemistry
From the journal Biological Chemistry Volume 397 Issue 9

Abstract

The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

Keywords: aspartyl protease; cathepsins; pericellular proteolysis; substrate specificity; tumor microenvironment; zymogen

Acknowledgments

A.J.O. and C.S.C. were supported by the Program for Breakthrough Biomedical Research (PBBR) and the Sandler Foundation. We gratefully acknowledge additional funds that were provided from NIH CA 185689, NIH CA 186077, and NIH CA 196276 to C.S.C. S.L.I was supported by NIH Pharmaceutical Sciences and Pharmacogenomics Training Grant T32GM008155.

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Supplemental Material:

The online version of this article (DOI: 10.1515/hsz-2016-0138) offers supplementary material, available to authorized users.

Received: 2016-2-12
Accepted: 2016-4-20
Published Online: 2016-5-4
Published in Print: 2016-9-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: proteolytic networks across cellular boundaries
  4. HIGHLIGHT: IPS 2015 – 9TH GENERAL MEETING OF THE INTERNATIONAL PROTEOLYSIS SOCIETY
  5. A personal journey with matrix metalloproteinases
  6. Type II transmembrane serine proteases as potential targets for cancer therapy
  7. Membrane trafficking and proteolytic activity of γ-secretase in Alzheimer’s disease
  8. Dipeptidyl peptidase 9 substrates and their discovery: current progress and the application of mass spectrometry-based approaches
  9. Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains
  10. Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors
  11. Granzyme B inhibits keratinocyte migration by disrupting epidermal growth factor receptor (EGFR)-mediated signaling
  12. Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1
  13. Probing catalytic rate enhancement during intramembrane proteolysis
  14. Human 20S proteasome activity towards fluorogenic peptides of various chain lengths
  15. Research Articles/Short Communications
  16. Protein Structure and Function
  17. Biophysical analysis of three novel profilin-1 variants associated with amyotrophic lateral sclerosis indicates a correlation between their aggregation propensity and the structural features of their globular state
  18. The potential of the Galleria mellonella innate immune system is maximized by the co-presentation of diverse antimicrobial peptides
https://doi.org/10.1515/hsz-2016-0138
Keywords for this article
aspartyl protease; cathepsins; pericellular proteolysis; substrate specificity; tumor microenvironment; zymogen

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: proteolytic networks across cellular boundaries
  4. HIGHLIGHT: IPS 2015 – 9TH GENERAL MEETING OF THE INTERNATIONAL PROTEOLYSIS SOCIETY
  5. A personal journey with matrix metalloproteinases
  6. Type II transmembrane serine proteases as potential targets for cancer therapy
  7. Membrane trafficking and proteolytic activity of γ-secretase in Alzheimer’s disease
  8. Dipeptidyl peptidase 9 substrates and their discovery: current progress and the application of mass spectrometry-based approaches
  9. Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains
  10. Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors
  11. Granzyme B inhibits keratinocyte migration by disrupting epidermal growth factor receptor (EGFR)-mediated signaling
  12. Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1
  13. Probing catalytic rate enhancement during intramembrane proteolysis
  14. Human 20S proteasome activity towards fluorogenic peptides of various chain lengths
  15. Research Articles/Short Communications
  16. Protein Structure and Function
  17. Biophysical analysis of three novel profilin-1 variants associated with amyotrophic lateral sclerosis indicates a correlation between their aggregation propensity and the structural features of their globular state
  18. The potential of the Galleria mellonella innate immune system is maximized by the co-presentation of diverse antimicrobial peptides
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