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Author (up) Hira, V.V.V.; Verbovsek, U.; Breznik, B.; Srdic, M.; Novinec, M.; Kakar, H.; Wormer, J.; der Swaan, B.V.; Lenarcic, B.; Juliano, L.; Mehta, S.; Van Noorden, C.J.F.; Lah, T.T. url  doi
  Title Cathepsin K cleavage of SDF-1alpha inhibits its chemotactic activity towards glioblastoma stem-like cells Type Journal Article
  Year 2017 Publication Biochimica et Biophysica Acta Abbreviated Journal Biochim Biophys Acta  
  Volume 1864 Issue 3 Pages 594-603  
  Keywords Amino Acid Sequence; Cathepsin K/genetics/*metabolism; Cell Line, Tumor; Chemokine CXCL12/chemistry/genetics/*metabolism; Chemotaxis; 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; *Cathepsin K; *Glioma stem-like cells; *Niche; *Stromal-derived factor-1alpha  
  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-1alpha (SDF-1alpha), 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-1alpha 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-1alpha cleavage by CatK inactivates SDF-1alpha and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1alpha after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1alpha at 3 sites in the N-terminus, which is the region of SDF-1alpha that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1alpha and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1alpha had chemotactic activity whereas CatK cleavage products of SDF-1alpha did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1alpha. 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.  
  Address Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Vecna 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, Vecna pot 113, 1000 Ljubljana, Slovenia  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0006-3002 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28040478 Approved no  
  Call Number ref @ user @ Serial 96615  
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