Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-11-04 DOI:10.1158/0008-5472.CAN-24-0134
Meng Jiao, Christopher J Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R Saban, Fang Li, Chuan-Yuan Li
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Abstract

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson's disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy.

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靶向儿茶酚-O-甲基转移酶可诱导线粒体功能障碍并提高胶质瘤放疗的疗效
放疗(RT)通常用于消除胶质瘤手术切除后残留的肿瘤细胞。然而,肿瘤复发是普遍现象,这凸显了开发治疗策略以提高神经胶质瘤放疗疗效的医疗需求尚未得到满足。关注目前已获批准的已知可穿过血脑屏障的药物的放射增敏潜力可促进快速临床转化。在这里,我们评估了儿茶酚-邻甲基转移酶(COMT)在胶质瘤治疗中的作用,它是降解儿茶酚胺的关键酶,也是帕金森病的药物靶点。TCGA数据分析显示,与正常脑组织相比,低级别胶质瘤和胶质母细胞瘤的COMT表达水平明显更高。通过基因敲除或FDA批准的COMT抑制剂抑制COMT,可使胶质瘤细胞在体外和体内对RT显著敏感。从机理上讲,抑制胶质瘤细胞中的 COMT 会导致线粒体功能障碍,增加线粒体 RNA 向细胞质的释放,激活细胞的抗病毒双链 RNA 传感途径和 I 型干扰素(IFN)反应。I 型干扰素的升高刺激了小胶质细胞的吞噬能力,增强了 RT 的疗效。考虑到 COMT 抑制剂长期以来建立的安全记录,这些发现为评估它们与 RT 联合治疗胶质瘤患者提供了可靠的依据。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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