Inhibition of circulating dipeptidyl peptidase 4 activity in patients with metastatic prostate cancer Journal Article

Authors: Nazarian, A.; Lawlor, K.; Yi, S. S.; Philip, J.; Ghosh, M.; Yaneva, M.; Villanueva, J.; Saghatelian, A.; Assel, M.; Vickers, A. J.; Eastham, J. A.; Scher, H. I.; Carver, B. S.; Lilja, H.; Tempst, P.
Article Title: Inhibition of circulating dipeptidyl peptidase 4 activity in patients with metastatic prostate cancer
Abstract: Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptidebased freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostatespecific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proofof- principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.
Journal Title: Molecular & Cellular Proteomics
Volume: 13
Issue: 11
ISSN: 1535-9476
Publisher: Amer Soc Biochemistry Molecular Biology Inc  
Date Published: 2014-11-01
Start Page: 3082
End Page: 3096
Language: English
DOI: 10.1074/mcp.M114.038836
PROVIDER: scopus
PMCID: PMC4223493
PUBMED: 25056937
Notes: Export Date: 1 December 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. Mousumi Ghosh
    2 Ghosh
  2. Hans Gosta Lilja
    305 Lilja
  3. Paul J Tempst
    323 Tempst
  4. Mariana M Yaneva
    9 Yaneva
  5. Andrew J Vickers
    625 Vickers
  6. James Eastham
    455 Eastham
  7. Brett Stewart Carver
    118 Carver
  8. San S Yi
    13 Yi
  9. Howard Scher
    979 Scher
  10. Kevin S Lawlor
    9 Lawlor
  11. John Philip
    25 Philip
  12. Melissa Jean Assel
    60 Assel