针对富马酸水合酶缺陷型癌症中 ABL1 介导的氧化应激适应的靶向治疗。
Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.
机构信息
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
出版信息
Cancer Cell. 2014 Dec 8;26(6):840-850. doi: 10.1016/j.ccell.2014.10.005.
Abstract
Patients with germline fumarate hydratase (FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes. Activity of the proto-oncogene ABL1 is upregulated in FH-deficient kidney tumors and drives a metabolic and survival signaling network necessary to cope with impaired mitochondrial function and abnormal accumulation of intracellular fumarate. Excess fumarate indirectly stimulates ABL1 activity, while restoration of wild-type FH abrogates both ABL1 activation and the cytotoxicity caused by ABL1 inhibition or knockdown. ABL1 upregulates aerobic glycolysis via the mTOR/HIF1α pathway and neutralizes fumarate-induced proteotoxic stress by promoting nuclear localization of the antioxidant response transcription factor NRF2. Our findings identify ABL1 as a pharmacologically tractable therapeutic target in glycolytically dependent, oxidatively stressed tumors.
摘要
携带种系琥珀酸水合酶 (FH) 突变的患者易发生侵袭性肾细胞癌，治疗选择有限，治疗效果不佳。原癌基因 ABL1 在 FH 缺陷的肾肿瘤中上调，驱动代谢和存活信号网络，以应对受损的线粒体功能和细胞内琥珀酸的异常积累。过量的琥珀酸间接刺激 ABL1 的活性，而野生型 FH 的恢复则消除 ABL1 的激活以及 ABL1 抑制或敲低引起的细胞毒性。ABL1 通过 mTOR/HIF1α 通路上调有氧糖酵解，并通过促进抗氧化反应转录因子 NRF2 的核定位来中和琥珀酸诱导的蛋白毒性应激。我们的研究结果表明，ABL1 是糖酵解依赖性、氧化应激肿瘤中一种具有潜在治疗价值的药物靶点。
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