title: Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells.
abstract: Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy.
authors.affiliation: Authors' Affiliations: Departments of Immunology, Radiation Oncology, and Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Choi
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schroeder
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bram
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D021983:Cyclophilins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D050778:NFATC Transcription Factors / Q000378:metabolism; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C081786:cyclophilin B; D001616:beta-Galactosidase; D021983:Cyclophilins