Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 21, Pages 6640-6649Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-0774
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Funding
- National Natural Science Foundation of China [81572472, 81401087, 81502494, 61402138]
- International S&T Cooperation Program of China [2014DFA31630]
- Natural Science Foundation of Heilongjiang Province [QC2014C099]
- Post-doctoral Foundation of Heilongjiang Province [LBH-Z16106]
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Purpose: Glioma-initiating cells (GIC) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development. Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays to detect signaling activity. Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds beta-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between b-catenin and TCF4, CypA enhances transcriptional activity. Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/beta-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. (C) 2017 AACR.
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