Cathepsin K cleavage of SDF-1[alpha] inhibits its chemotactic activity towards glioblastoma stem-like cellsHira, Vashendriya V. V. (Avtor) Verbovšek, Urška (Avtor) Breznik, Barbara (Avtor) Srdič, Matic (Avtor) Novinec, Marko (Avtor) Kakar, Hala (Avtor) Wormer, Jill (Avtor) Swaan, Britt van der (Avtor) Lenarčič, Brigita (Avtor) Juliano, Luiz (Avtor) Mehta, Shwetal (Avtor) Noorden, Cornelis J. F. van (Avtor) Lah Turnšek, Tamara (Avtor) glioma stem-like cellsnichestromal derived factor-[alpha]cathepsin KGlioblastoma (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.20172024-07-24 03:47:26Neznano19721UDK: 577.2ISSN pri članku: 0167-4889DOI: 10.1016/j.bbamcr.2016.12.021COBISS_ID: 4162895sl