mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability

Alexander J. Valvezan; Marc Turner; Amine Belaid; Hilaire C. Lam; Spencer K. Miller; Molly C. McNamara; Christian Baglini; Benjamin E. Housden; Norbert Perrimon; David J. Kwiatkowski; John M. Asara; Elizabeth P. Henske; Brendan D. Manning

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mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability

机译：MTORC1将核苷酸合成对核苷酸的需求致敬，导致有可命性的代谢脆弱性

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Summary The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. We find that pharmacological inhibitors of guanylate nucleotide synthesis have selective deleterious effects on TSC-deficient cells, including in mouse tumor models. This effect stems from replication stress and DNA damage caused by mTORC1-driven rRNA synthesis, which renders nucleotide pools limiting. These findings reveal a metabolic vulnerability downstream of mTORC1 triggered by anabolic imbalance. Graphical Abstract Display Omitted Highlights ? IMPDH inhibition selectively kills TSC2-deficient cells in an mTORC1-dependent manner ? The IMPDH inhibitor mizoribine has anti-tumor effects in in?vivo models of TSC ? IMPDH inhibition causes replication stress and DNA damage in TSC-deficient cells ? mTORC1-driven rRNA synthesis sensitizes cells to inhibition of nucleotide synthesis mTORC1 drives anabolic tumor metabolism, including ribosome biogenesis and nucleotide synthesis. Valvezan et?al. show that blocking synthesis of guanine nucleotides while sustaining mTORC1 activity depletes nucleotide pools, causing DNA replication stress and apoptosis in mTORC1-driven tumor models.

机译：发明内容雷帕霉素复合物1（MTORC1）的机械靶通过并行诱导关键的合成代谢过程，包括蛋白质，脂质和核苷酸合成来支持增殖。我们假设这些过程偶联以维持在具有MTORC1活化的细胞中的合成代谢平衡，人类癌症中的常见事件。结核硬化复合体（TSC）肿瘤抑制剂的损失导致MTORC1的激活和肿瘤综合征TSC的发育。我们发现胍基核苷酸合成的药理学抑制剂对TSC缺陷细胞具有选择性有害影响，包括小鼠肿瘤模型。这种效果源于MTORC1驱动的RRNA合成引起的复制应力和DNA损伤，其使核苷酸库限制呈现。这些发现揭示了通过代谢不平衡触发的MTORC1下游的代谢漏洞。图形抽象显示省略了亮点？ IMPDH抑制选择性地以MTORC1依赖性方式杀死TSC2缺陷的细胞？ IMIzoribine的IMPDH抑制剂在TSC的体内模型中具有抗肿瘤作用吗？ IMPDH抑制导致TSC缺陷细胞中的复制应力和DNA损伤？ MTORC1驱动的RRNA合成使细胞敏感到核苷酸合成MTORC1的抑制作用核糖肿瘤代谢，包括核糖体生物发生和核苷酸合成。 valepan等。显示阻断鸟嘌呤核苷酸的合成，同时维持MTORC1活性耗尽核苷酸库，导致MTORC1驱动肿瘤模型中的DNA复制应力和凋亡。

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来源
《Cancer Cell》 |2017年第5期|共15页
作者
Alexander J. Valvezan; Marc Turner; Amine Belaid; Hilaire C. Lam; Spencer K. Miller; Molly C. McNamara; Christian Baglini; Benjamin E. Housden; Norbert Perrimon; David J. Kwiatkowski; John M. Asara; Elizabeth P. Henske; Brendan D. Manning;
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作者单位

Department of Genetics and Complex Diseases Harvard T.H. Chan School of Public Health;

Department of Genetics and Complex Diseases Harvard T.H. Chan School of Public Health;

Department of Medicine Brigham and Women's Hospital and Harvard Medical School;

Department of Medicine Brigham and Women's Hospital and Harvard Medical School;

Department of Genetics and Complex Diseases Harvard T.H. Chan School of Public Health;

Department of Genetics and Complex Diseases Harvard T.H. Chan School of Public Health;

Department of Medicine Brigham and Women's Hospital and Harvard Medical School;

Department of Genetics Harvard Medical School;

Department of Genetics Harvard Medical School;

Department of Medicine Brigham and Women's Hospital and Harvard Medical School;

Division of Signal Transduction Beth Israel Deaconess Medical Center Department of Medicine;

Department of Medicine Brigham and Women's Hospital and Harvard Medical School;

Department of Genetics and Complex Diseases Harvard T.H. Chan School of Public Health;

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正文语种 eng
中图分类肿瘤学;
关键词
mTOR; rapamycin; tumor metabolism; tuberous sclerosis complex; TSC2; IMPDH; mizoribine; mycophenolic acid; nucleotide synthesis; lymphangioleiomyomatosis;

机译：MTOR;雷帕霉素;肿瘤代谢;肿块硬化复合体;TSC2;IMPDH;MIZORIBINE;霉菌酸;核苷酸合成;淋巴基胆管瘤;

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专利

1. mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability [J] . Alexander J. Valvezan, Marc Turner, Amine Belaid, Cancer Cell . 2017,第5期

机译：MTORC1将核苷酸合成对核苷酸的需求致敬，导致有可命性的代谢脆弱性
2. Fluorine -Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis [J] . Ravindra Manasa, Wilson Mike R., Tong Nian, Journal of Medicinal Chemistry . 2018,第9期

机译：氟 - 取出的吡咯并通过叶酸受体α和质子偶联叶酸转运蛋白通过细胞吸收靶向靶向丙米胺类似物，并抑制De Novo嘌呤核苷酸生物合成
3. Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolates via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis [J] . Manasa Ravindra, Adrianne Wallace-Povirk, Mohammad A. Karim, Journal of Medicinal Chemistry . 2018,第5期

机译：用新型吡啶基6-取代的吡咯并通过叶酸受体α和质子偶联叶酸叶酸转运蛋白通过细胞摄取和抑制脱诺夫（Novo）的肿瘤靶向靶向吡啶基6-取代的吡咯烷[2,3- d〜1]嘧啶。 >嘌呤核苷酸生物合成
4. Detection of Single Nucleotide Variations and Copy Number Variations in Breast Cancer Samples Using Single Nucleotide Polymorphism-Targeted Massively Multiplexed PCR [C] . Zachary Demko, Bernhard G. Zimmermann, Eser Kirkizlar, International Molecular Medicine Tri-Conference. . 2015

机译：使用单核苷酸多态性靶向大规模多重PCR检测单核苷酸变化和乳腺癌样品的拷贝数变化
5. Development of Novel Cancer Treatments Targeting Pyrimidine Nucleotide Biosynthesis and the Synthesis of Tool Compounds for Enhanced Profiling of Oxidative Post-translational Modifications [D] . Pan, Roy David. 2021

机译：开发靶向嘧啶核苷酸生物合成的新型癌症治疗和工具化合物的合成，用于增强氧化翻译后修饰的分析
6. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability [O] . Alexander J. Valvezan, Marc Turner, Amine Belaid, -1

机译：mTORC1将核苷酸合成与核苷酸需求结合在一起从而导致可靶向的代谢脆弱性
7. mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability [O] . Alexander J. Valvezan, Marc Turner, Amine Belaid, 2017

机译：MTORC1将核苷酸合成对核苷酸的需求致敬，导致有可命性的代谢脆弱性

mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability

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