Remodelling of the translatome controls diet and its impact on tumorigenesis

<p style="font-family: Arial, sans-serif; font-size: 2.2em; font-weight: bolder; color:#0e6eB8;">Affiliations</p>
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<li style="list-style: decimal; margin-bottom: 8px;">Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA.</li><li style="list-style: decimal; margin-bottom: 8px;">School of Medicine and Department of Urology, UCSF, San Francisco, CA, USA.</li><li style="list-style: decimal; margin-bottom: 8px;">Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA, USA.</li><li style="list-style: decimal; margin-bottom: 8px;">Cardiovascular Research Institute, UCSF, San Francisco, CA, USA.</li><li style="list-style: decimal; margin-bottom: 8px;">Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA.</li><li style="list-style: decimal; margin-bottom: 8px;">Metabolomics Platform, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA.</li><li style="list-style: decimal; margin-bottom: 8px;">Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA. Davide.Ruggero@ucsf.edu.</li><li style="list-style: decimal; margin-bottom: 8px;">School of Medicine and Department of Urology, UCSF, San Francisco, CA, USA. Davide.Ruggero@ucsf.edu.</li><li style="list-style: decimal; margin-bottom: 8px;">Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA, USA. Davide.Ruggero@ucsf.edu.</li>
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<p id="PMID" style="font-family: Arial, sans-serif; font-size: 1.4em;">PMID:&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/39143206/" rel="nofollow" style="color: #0049B0; font-weight: 700;" target="_blank">39143206</a>&nbsp;DOI:&nbsp;<a href="https://doi.org/10.1038/s41586-024-07781-7" rel="nofollow" style="color: #0049B0; font-weight: 700;" target="_blank">10.1038/s41586-024-07781-7</a></p>

<p style="font-family: Arial, sans-serif; font-size: 2.2em; font-weight: bolder; color:#0e6eB8;">Abstract</p>
<p style="font-family: Arial, sans-serif; font-size: 1.4em;">Fasting is associated with a range of health benefits1,2,3,4,5,6. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting7,8. We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5′ untranslated regions (5′ UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK–MNK–eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source9,10 that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.</p><p style="font-family: Arial, sans-serif; font-size: 1.4em;">禁食与一系列健康益处相关联。然而，禁食如何通过信号传导改变蛋白质组以建立代谢程序仍然了解甚少。我们发现，在禁食期间，肝细胞会选择性地重塑转译组，而全局翻译却出现了矛盾性地下调。我们发现，真核翻译起始因子4E（eIF4E）的磷酸化（P-eIF4E）在禁食期间被诱导。我们展示了P-eIF4E在控制参与脂质分解和酮体生成的基因翻译方面的作用。抑制P-eIF4E会损害禁食和生酮饮食对酮体生成的响应。P-eIF4E通过其5′非翻译区（5′ UTRs）中的特定翻译调控元件调控这些信使RNA。我们的研究揭示了脂肪酸的新信号特性，在禁食期间脂肪酸水平升高。我们发现脂肪酸能够结合并诱导AMP激酶（AMPK）的激酶活性，从而增强MAP激酶相互作用蛋白激酶（MNK）的磷酸化，而MNK是磷酸化eIF4E的激酶。AMPK–MNK–eIF4E轴控制酮体生成，揭示了一个新的脂质介导的激酶信号通路，将酮体生成与翻译控制联系起来。某些类型的癌症利用酮体作为能量来源，这可能依赖于P-eIF4E。我们的研究发现，在生酮饮食下，eFT508（也称为tomivosertib；一种P-eIF4E抑制剂）能抑制胰腺肿瘤的生长。因此，我们的发现揭示了一个新的脂肪酸诱导信号通路，该通路激活选择性翻译，作为生酮生成的基础，并为癌症提供了一种量身定制的饮食干预疗法。</p><p style="font-family: Arial, sans-serif; font-size: 1.4em;"><b>关键词：</b>生酮饮食, 清除肿瘤</p>

<p style="font-family: Arial, sans-serif; font-size: 2.2em; font-weight: bolder; color:#0e6eB8;">References&nbsp;</p>
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