β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer.
β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer.
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β-连环蛋白-IRP2 引发的铁对线粒体代谢的可用性可用于治疗活性 β-连环蛋白介导的癌症
DOI：
10.1186/s12967-023-03914-0
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发表时间：
2023-01-26
影响因子：
7.4
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Wu, Yuting;Yang, Shuhui;Han, Luyang;Shang, Kezhuo;Zhang, Baohui;Gai, Xiaochen;Deng, Weiwei;Liu, Fangming;Zhang, Hongbing
尽管β-连环蛋白信号级联在人类癌症中经常发生改变，但针对这一通路的治疗尚未被批准用于癌症治疗。
对美国食品药品监督管理局（FDA）批准的药物库进行了高通量筛选，以确定能选择性抑制具有激活的β - 连环蛋白的细胞的治疗药物。评估了铁螯合剂和线粒体抑制剂在抑制细胞增殖和肿瘤发生方面的功效。测量了细胞内可螯合铁的水平，以深入了解具有激活的β - 连环蛋白的细胞对铁剥夺的潜在易感性。对线粒体功能进行了细胞外通量分析，以评估铁剥夺的下游事件。进行了染色质免疫沉淀、实时定量聚合酶链反应和免疫印迹实验，以确定β - 连环蛋白的作用靶点。对铁调节蛋白2（IRP2，细胞内铁稳态的关键调节因子）进行了耗竭实验，以阐明其在具有激活的β - 连环蛋白的细胞中的重要性。分析了在线数据库中人类癌症中β - 连环蛋白活性与IRP2 - 转铁蛋白受体1（TfR1）轴之间的相关性。
铁螯合剂被确定为针对具有激活的β - 连环蛋白的细胞的选择性抑制剂。甲磺酸去铁胺（一种铁螯合剂）优先抑制了具有激活的β - 连环蛋白的细胞在小鼠体内的增殖和肿瘤形成。从机制上讲，β - 连环蛋白刺激IRP2的转录，从而增加不稳定铁的水平。IRP2结合的铁的耗竭损害了由β - 连环蛋白增强的线粒体功能。此外，线粒体抑制剂S - Gboxin选择性地降低了与β - 连环蛋白相关的细胞活力和肿瘤形成。
β - 连环蛋白/IRP2/铁对线粒体能量学的刺激是β - 连环蛋白增强型癌症的可靶向的弱点。
网络版包含补充材料，可在10.1186/s12967 - 023 - 03914 - 0获取。
Although β-catenin signaling cascade is frequently altered in human cancers, targeting this pathway has not been approved for cancer treatment. High-throughput screening of an FDA-approved drug library was conducted to identify therapeutics that selectively inhibited the cells with activated β-catenin. Efficacy of iron chelator and mitochondrial inhibitor was evaluated for suppression of cell proliferation and tumorigenesis. Cellular chelatable iron levels were measured to gain insight into the potential vulnerability of β-catenin-activated cells to iron deprivation. Extracellular flux analysis of mitochondrial function was conducted to evaluate the downstream events of iron deprivation. Chromatin immunoprecipitation, real-time quantitative PCR and immunoblotting were performed to identify β-catenin targets. Depletion of iron-regulatory protein 2 (IRP2), a key regulator of cellular iron homeostasis, was carried out to elucidate its significance in β-catenin-activated cells. Online databases were analyzed for correlation between β-catenin activity and IRP2-TfR1 axis in human cancers. Iron chelators were identified as selective inhibitors against β-catenin-activated cells. Deferoxamine mesylate, an iron chelator, preferentially repressed β-catenin-activated cell proliferation and tumor formation in mice. Mechanically, β-catenin stimulated the transcription of IRP2 to increase labile iron level. Depletion of IRP2-sequered iron impaired β-catenin-invigorated mitochondrial function. Moreover, mitochondrial inhibitor S-Gboxin selectively reduced β-catenin-associated cell viability and tumor formation. β-catenin/IRP2/iron stimulation of mitochondrial energetics is targetable vulnerability of β-catenin-potentiated cancer. The online version contains supplementary material available at 10.1186/s12967-023-03914-0.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
4
作者：
通讯作者：
--
影响因子：
8
作者：
Coombs, G. S.;Schmitt, A. A.;Canning, C. A.;Alok, A.;Low, I. C. C.;Banerjee, N.;Kaur, S.;Utomo, V.;Jones, C. M.;Pervaiz, S.;Toone, E. J.;Virshup, D. M.
通讯作者：
Virshup, D. M.
影响因子：
7.4
作者：
Bilir B;Kucuk O;Moreno CS
通讯作者：
Moreno CS
影响因子：
6
作者：
Fiorillo, Marco;Toth, Fanni;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.