Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets
Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets
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DOI：
10.1038/cdd.2016.116
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发表时间：
2017-02-01
影响因子：
12.4
通讯作者：
Danial, Nika N.
中科院分区：
文献类型：
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作者：
Norberg, Erik;Lako, Ana;Danial, Nika N.
弥漫性大b细胞淋巴瘤（DLBCLs）是一种高度异质性的肿瘤，其亚群具有基因表达谱和代谢指纹所揭示的分子特征。虽然b细胞受体（BCR）依赖的DLBCLs是糖酵解的，但OxPhos-DLBCLs依赖于线粒体能量转导和营养利用途径，提供独立于BCR信号传导的促生存益处。与BCR-DLBCLs相比，OxPhos-DLBCLs中线粒体电子传递链（ETC）活性升高是这些代谢差异的组成部分，这与ETC成分的蛋白质丰度更高有关。为了深入了解oxphos - dlbcl中ETC活性选择性增加的分子决定因素及其对线粒体能量代谢的依赖，我们研究了负责合成编码ETC亚基的线粒体DNA的线粒体翻译途径。定量质谱分析发现，与BCR亚型相比，OxPhos-DLBCL中线粒体翻译因子的表达增加。生化和功能分析表明，线粒体翻译途径是增加OxPhos-DLBCL中ETC活性和线粒体能量储备所必需的。重要的是，使用RNA干扰或fda批准的抑制剂替加环素（Tigecyl）对线粒体翻译途径进行药理学扰动来减少几种线粒体翻译蛋白的分子缺失，对OxPhos-DLBCL细胞系和原发性肿瘤具有选择性毒性。这些发现为oxphos - dlbcl的代谢特性提供了更多的分子见解，并标志着线粒体翻译途径是这些肿瘤的潜在治疗靶点。
Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhos-DLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors.