Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/β-Catenin Signaling

Abstract

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. 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. In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds β-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between β-catenin and TCF4, CypA enhances transcriptional activity. Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/β-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. .

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…A contribution of FKBP4 to cancer stemness manifestations, such as self-renewal, spheroid formation, and chemoresistance, has been reported as well [181,182]. Meanwhile, a pivotal role of cyclophilin A in maintaining stemness in gliomas has been established: By means of direct binding to β-catenin, cyclophilin A regulates the interactions of β-catenin with Wnt target gene promoters and TCF4, thus resulting in an enhancement of transcriptional activity [198]. It follows from the latter publication that cyclophilin A promotes the self-renewal and radioresistance of neurosphere-forming (CSC-like) glioma cells through stimulating the Wnt/β-catenin pathway [198].…”

“…Meanwhile, a pivotal role of cyclophilin A in maintaining stemness in gliomas has been established: By means of direct binding to β-catenin, cyclophilin A regulates the interactions of β-catenin with Wnt target gene promoters and TCF4, thus resulting in an enhancement of transcriptional activity [198]. It follows from the latter publication that cyclophilin A promotes the self-renewal and radioresistance of neurosphere-forming (CSC-like) glioma cells through stimulating the Wnt/β-catenin pathway [198]. Even the intramitochondrial peptidyl-prolyl isomerase cyclophilin D may be involved in activating the motility, invasive, and pro-metastatic properties of CSCs, as was suggested by Senturk et al [193].…”

Wnt/β‐catenin signaling cascade: A promising target for glioma therapy

“…Cyclophilin A (CypA), the major intracellular target of the immunosuppressive drug cyclosporin A (CsA), promotes GIC stemness, self‐renewal, and radioresistance through Wnt/β‐catenin signaling (G. Wang, Shen, et al, ). As a Food and Drug Administration (FDA) approved drug, quetiapine (QUE) accelerates the GSCs differentiation into oligodendrocyte via inhibition of Wnt signaling (Y. Wang, Huang, et al, ).…”

MicroRNA‐1275 induces radiosensitization in oesophageal cancer by regulating epithelial‐to‐mesenchymal transition via Wnt/β‐catenin pathway

“…37 Furtherly, recent researches have highlighted the participation of Wnt/β-catenin pathway not only in cancer progression 37,38 but also in the development of radiation resistance in numerous carcinomas. 39,40 Also, the interplay between miRNAs and Wnt/β-catenin pathway in regulating EMT has also been indicated before. 41 Presently, we discovered this pathway also mediated the influence of miR-1275 on EC cell radioresistance.…”