20.500.12556/DiRROS-19721 Cathepsin K cleavage of SDF-1[alpha] inhibits its chemotactic activity towards glioblastoma stem-like cells 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. glioma stem-like cells niche stromal derived factor-[alpha] cathepsin K true false true Angleški jezik Ni določen Neznano 2024-07-24 03:47:26 2024-07-24 15:02:09 2024-07-25 04:14:58 0000-00-00 00:00:00 2017 0 0 str. 594-603 no. 3 Vol. 1864 2017 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 2017-03-01 577.2 0167-4889 10.1016/j.bbamcr.2016.12.021 4162895 RAZ_Hira_Vashendriya_V._V._2017.pdf RAZ_Hira_Vashendriya_V._V._2017.pdf 1 0C77AF127CDD15F7B794A90908A4AB00 34dc75fbbb58aaf4c21b780acc84ed482f732c66717d492d25decdeaac97f3c7 ae226e76-49ac-11ef-b487-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=27371 https://doi.org/10.1016/j.bbamcr.2016.12.021 0 bbadea80-49ac-11ef-b487-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=27372 Nacionalni inštitut za biologijo 0 0 0