Cathepsin K Cleavage Of Sdf-1Î± 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-1Î± (SDF-1Î±), 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-1Î± 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-1Î± cleavage by CatK inactivates SDF-1Î± and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1Î± after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1Î± at 3 sites in the N-terminus, which is the region of SDF-1Î± that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1Î± and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1Î± had chemotactic activity whereas CatK cleavage products of SDF-1Î± did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1Î±. 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.
Biochimica et Biophysica Acta - Molecular Cell Research
Digital Object Identifier (DOI)
Hira, Vashendriya V.V.; VerbovÅ¡ek, UrÅ¡ka; Breznik, Barbara; SrdiÄ, Matic; Novinec, Marko; Kakar, Hala; Wormer, Jill; Van der Swaan, Britt; LenarÄiÄ, Brigita; Juliano, Luiz; Mehta, Shwetal; Van, Cornelis J.F.; and Lah, Tamara T., "Cathepsin K Cleavage Of Sdf-1Î± Inhibits Its Chemotactic Activity Towards Glioblastoma Stem-Like Cells" (2017). Neurobiology. 293.