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Title:Cathepsin K cleavage of SDF-1[alpha] inhibits its chemotactic activity towards glioblastoma stem-like cells
Authors:ID Hira, Vashendriya V. V. (Author)
ID Verbovšek, Urška (Author)
ID Breznik, Barbara (Author)
ID Srdič, Matic (Author)
ID Novinec, Marko (Author)
ID Kakar, Hala (Author)
ID Wormer, Jill (Author)
ID Swaan, Britt van der (Author)
ID Lenarčič, Brigita (Author)
ID Juliano, Luiz (Author)
ID Mehta, Shwetal (Author)
ID Noorden, Cornelis J. F. van (Author)
ID Lah Turnšek, Tamara (Author)
Files:.pdf PDF - Presentation file, download (1,50 MB)
MD5: 0C77AF127CDD15F7B794A90908A4AB00
 
URL URL - Source URL, visit https://doi.org/10.1016/j.bbamcr.2016.12.021
 
Language:English
Typology:1.01 - Original Scientific Article
Organization:Logo NIB - National Institute of Biology
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:glioma stem-like cells, niche, stromal derived factor-[alpha], cathepsin K
Publication status:Published
Publication version:Version of Record
Publication date:01.03.2017
Year of publishing:2017
Number of pages:str. 594-603
Numbering:Vol. 1864, no. 3
PID:20.500.12556/DiRROS-19721 New window
UDC:577.2
ISSN on article:0167-4889
DOI:10.1016/j.bbamcr.2016.12.021 New window
COBISS.SI-ID:4162895 New window
Publication date in DiRROS:24.07.2024
Views:472
Downloads:303
Metadata:XML DC-XML DC-RDF
:
HIRA, Vashendriya V. V., VERBOVŠEK, Urška, BREZNIK, Barbara, SRDIČ, Matic, NOVINEC, Marko, KAKAR, Hala, WORMER, Jill, SWAAN, Britt van der, LENARČIČ, Brigita, JULIANO, Luiz, MEHTA, Shwetal, NOORDEN, Cornelis J. F. van and LAH TURNŠEK, Tamara, 2017, Cathepsin K cleavage of SDF-1[alpha] inhibits its chemotactic activity towards glioblastoma stem-like cells. Biochimica et biophysica acta : Molecular cell research [online]. 2017. Vol. 1864, no. 3, p. 594–603. [Accessed 8 April 2025]. DOI 10.1016/j.bbamcr.2016.12.021. Retrieved from: https://dirros.openscience.si/IzpisGradiva.php?lang=eng&id=19721
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Record is a part of a journal

Title:Biochimica et biophysica acta : Molecular cell research
Shortened title:Biochim. biophys. acta, Mol. cell res.
Publisher:Elsevier
ISSN:0167-4889
COBISS.SI-ID:5342727 New window

Document is financed by a project

Funder:ARIS - Slovenian Research and Innovation Agency
Project number:P1-0245-2015
Name:Ekotoksiologija, toksikološka genomika in karcinogeneza
Funder:ARIS - Slovenian Research and Innovation Agency
Project number:P1-0140-2015
Name:Proteoliza in njena regulacija
Funder:Other - Other funder or multiple funders
Funding programme:René Vogels travel grant (VVVH)
Funder:Other - Other funder or multiple funders
Funding programme:JoKolk scholarship (VVVH)
Funder:Other - Other funder or multiple funders
Funding programme:Dutch Cancer Society
Project number:UVA 2014-6839
Funder:ARIS - Slovenian Research and Innovation Agency
Funding programme:Young Researchers Grant
Funder:EC - European Commission
Funding programme:Fundação de Amparo à Pesquisa do Estado de São Paulo
Project number:FAPESP-12/50191-AR

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License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

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