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Photoactivated inhibition of cathepsin K in a 3D tumor model

  • Mackenzie K. Herroon , Rajgopal Sharma , Erandi Rajagurubandara , Claudia Turro , Jeremy J. Kodanko EMAIL logo and Izabela Podgorski EMAIL logo
Published/Copyright: February 20, 2016
Biological Chemistry
From the journal Biological Chemistry Volume 397 Issue 6

Abstract

Collagenolytic activity of cathepsin K is important for many physiological and pathological processes including osteoclast-mediated bone degradation, macrophage function and fibroblast-mediated matrix remodeling. Here, we report application of a light-activated inhibitor for controlling activity of cathepsin K in a 3D functional imaging assay. Using prostate carcinoma cell line engineered to overexpress cathepsin K, we demonstrate the utility of the proteolytic assay in living tumor spheroids for the evaluation and quantification of the inhibitor effects on cathepsin K-mediated collagen I degradation. Importantly, we also show that utilizing the ruthenium-caged version of a potent nitrile cathepsin K inhibitor (4), cis-[Ru(bpy)2(4)2](BF4)2 (5), offers significant advantage in terms of effective concentration of the inhibitor and especially its light-activated control in the 3D assay. Our results suggest that light activation provides a suitable, attractive approach for spatial and temporal control of proteolytic activity, which remains a critical, unmet need in treatment of human diseases, especially cancer.

Keywords: cathepsin K; 3D tumor model; photoactivation; prostate cancer; proteolysis; ruthenium-caged inhibitors

Funding source: National Institutes of Health

Award Identifier / Grant number: EB 016072

Funding statement: We thank the National Institutes of Health (Grant EB 016072) and Wayne State University (Rumble Fellowship to R.S.) for their generous funding of this research.

Acknowledgments

We thank the National Institutes of Health (Grant EB 016072) and Wayne State University (Rumble Fellowship to R.S.) for their generous funding of this research.

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Received: 2015-11-10
Accepted: 2016-2-16
Published Online: 2016-2-20
Published in Print: 2016-6-1

©2016 by De Gruyter

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https://doi.org/10.1515/hsz-2015-0274
Keywords for this article
cathepsin K; 3D tumor model; photoactivation; prostate cancer; proteolysis; ruthenium-caged inhibitors

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Neutrophils in cystic fibrosis
  4. Role of reverse transendothelial migration of neutrophils in inflammation
  5. Minireview
  6. MicroRNA regulation of airway smooth muscle function
  7. Research Articles/Short Communications
  8. Protein Structure and Function
  9. Human CYP27A1 catalyzes hydroxylation of β-sitosterol and ergosterol
  10. Molecular Medicine
  11. Expression of MIF and CD74 in leukemic cell lines: correlation to DR expression destiny
  12. Clinical evaluation of microRNA-145 expression in renal cell carcinoma: a promising molecular marker for discriminating and staging the clear cell histological subtype
  13. Cell Biology and Signaling
  14. Identification of protein phosphatase 2A as an interacting protein of leucine-rich repeat kinase 2
  15. Characterization of the nuclear import mechanisms of HSV-1 UL31
  16. Human dipeptidyl peptidase III regulates G-protein coupled receptor-dependent Ca2+ concentration in human embryonic kidney 293T cells
  17. Proteolysis
  18. Photoactivated inhibition of cathepsin K in a 3D tumor model
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