Title

Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells

Authors

Vashendriya V. Hira, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands; Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: v.v.hira@amc.uva.nl.
Urška Verbovšek, Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
Barbara Breznik, Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia; Jozef Stefan International Postgraduate School, Jamova 39, 1000 Ljubljana, Slovenia.
Matic Srdič, Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
Marko Novinec, Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
Hala Kakar, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Jill Wormer, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Britt Van der Swaan, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Brigita Lenarčič, Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
Luiz Juliano, Department of Biophysics, Medical School, Federal University of Sao Paolo, Brazil.
Shwetal Mehta, Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Cornelis J. Van Noorden, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Tamara T. Lah, Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia; Jozef Stefan International Postgraduate School, Jamova 39, 1000 Ljubljana, Slovenia; Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.

Document Type

Article

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation.

Keywords

Cathepsin K, Glioma stem-like cells, Niche, Stromal-derived factor-1α

Medical Subject Headings

Amino Acid Sequence; Benzylamines; Cathepsin K (genetics, metabolism); Cell Line, Tumor; Chemokine CXCL12 (chemistry, genetics, metabolism); Chemotaxis; Cyclams; Gene Expression; Heterocyclic Compounds (pharmacology); Humans; Neoplastic Stem Cells (metabolism, pathology); Neuroglia (metabolism, pathology); Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Proteolysis; Receptors, CXCR (genetics, metabolism); Receptors, CXCR4 (antagonists & inhibitors, genetics, metabolism); Stem Cell Niche (genetics)

Publication Date

3-1-2017

Publication Title

Biochimica et biophysica acta. Molecular cell research

ISSN

0167-4889

Volume

1864

Issue

3

First Page

594

Last Page

603

PubMed ID

28040478

Digital Object Identifier (DOI)

10.1016/j.bbamcr.2016.12.021

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