Authors' Affiliations: Departments of Immunology, Radiation Oncology, and Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.
Cancer Res. 2014 Jan 15;74(2):484-96. doi: 10.1158/0008-5472.CAN-13-0771. Epub 2013 Nov 22.
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.
多形性胶质母细胞瘤是一种侵袭性的、治疗耐药的脑肿瘤,因此确定有效的治疗靶点仍然很重要。在这里,我们报告细胞色素 P450B(CypB),一种驻留在内质网(ER)中的脯氨酰异构酶,为多形性胶质母细胞瘤细胞提供了一个重要的生存信号。对基因表达数据库的分析表明,CypB 在许多恶性神经胶质瘤病例中上调。我们发现,抑制 CypB 可减少体外和体内人多形性胶质母细胞瘤细胞的增殖和存活。我们还发现,用细胞色素 P450 抑制剂,包括已批准的药物环孢素,治疗可大大降低多形性胶质母细胞瘤细胞的活力。从机制上讲,CypB 的耗竭或药理学抑制会导致致癌性 RAS-丝裂原激活蛋白激酶途径的过度激活、细胞衰老信号的诱导以及 MYC、突变型 p53、Chk1 和 Janus 激活激酶/STAT3 信号的丧失导致的死亡。CypB 耗尽的多形性胶质母细胞瘤细胞中活性氧、内质网扩张和异常未折叠蛋白反应的升高表明,CypB 减轻氧化和内质网应激,并协调应激适应反应。CypB 下游增强的细胞存活和多种致癌蛋白的持续表达可能导致多形性胶质母细胞瘤肿瘤的不良预后。我们的研究结果将内质网中伴侣介导的蛋白质折叠与致癌转化的机制联系起来,使 CypB 成为多形性胶质母细胞瘤治疗的一个有吸引力和可立即靶向的分子。