Section of Neurosurgery, Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Sci Transl Med. 2018 Jul 4;10(448). doi: 10.1126/scitranslmed.aar2238.
The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated -methylguanine DNA methyltransferase () promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.
胶质母细胞瘤患者对烷化剂化疗的反应存在异质性。然而，目前尚无普遍接受的预测这些药物对患者反应的指标。我们发现核因子 κB（NF-κB）共调节子 B 细胞慢性淋巴细胞白血病/淋巴瘤 3（BCL-3）是替莫唑胺（TMZ）治疗反应的独立预测因子。在肿瘤具有甲基化 -甲基鸟嘌呤 DNA 甲基转移酶（）启动子的胶质母细胞瘤患者中，BCL-3 高表达与 TMZ 反应不良相关。从机制上讲，BCL-3 通过启动子特异性 NF-κB 二聚体交换诱导胶质母细胞瘤中的上皮间质转化，促进更恶性的表型。碳酸酐酶 II（CAII）被鉴定为促进 BCL-3 介导的化疗耐药的下游因子。胶质母细胞瘤异种移植小鼠模型中的实验表明，CAII 抑制剂乙酰唑胺增强了 TMZ 治疗动物的存活。我们的数据表明，BCL-3 可能是胶质母细胞瘤对烷化剂化疗反应的有用指标，乙酰唑胺可能被重新用作治疗 TMZ 耐药胶质母细胞瘤的化疗增敏剂。
