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禁食通过p53依赖的代谢协同作用改善肝细胞癌的治疗反应。

Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism.

作者信息

Krstic Jelena, Reinisch Isabel, Schindlmaier Katharina, Galhuber Markus, Riahi Zina, Berger Natascha, Kupper Nadja, Moyschewitz Elisabeth, Auer Martina, Michenthaler Helene, Nössing Christoph, Depaoli Maria R, Ramadani-Muja Jeta, Usluer Sinem, Stryeck Sarah, Pichler Martin, Rinner Beate, Deutsch Alexander J A, Reinisch Andreas, Madl Tobias, Chiozzi Riccardo Zenezini, Heck Albert J R, Huch Meritxell, Malli Roland, Prokesch Andreas

机构信息

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Austria.

Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria.

出版信息

Sci Adv. 2022 Jan 21;8(3):eabh2635. doi: 10.1126/sciadv.abh2635.

DOI:10.1126/sciadv.abh2635
PMID:35061544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8782451/
Abstract

Cancer cells voraciously consume nutrients to support their growth, exposing metabolic vulnerabilities that can be therapeutically exploited. Here, we show in hepatocellular carcinoma (HCC) cells, xenografts, and patient-derived organoids that fasting improves sorafenib efficacy and acts synergistically to sensitize sorafenib-resistant HCC. Mechanistically, sorafenib acts noncanonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR signaling, prevents this Warburg shift. Regulating glucose transporter and proapoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage HCC.

摘要

癌细胞会大量消耗营养物质以支持其生长，从而暴露出可用于治疗的代谢弱点。在此，我们在肝癌（HCC）细胞、异种移植瘤以及患者来源的类器官中发现，禁食可提高索拉非尼的疗效，并协同作用使对索拉非尼耐药的肝癌细胞敏感。从机制上讲，索拉非尼作为线粒体呼吸的非典型抑制剂发挥作用，导致耐药细胞依赖糖酵解来维持生存。禁食通过降低葡萄糖水平并阻碍AKT/mTOR信号传导，阻止了这种瓦伯格效应转变。p53通过调节葡萄糖转运蛋白和促凋亡蛋白的表达，对于禁食使索拉非尼敏感的效应是必要且充分的。p53对于在原位肝癌小鼠模型中禁食介导的索拉非尼疗效改善也至关重要。总之，我们的数据表明，对于具有完整p53信号传导的肝癌，禁食和索拉非尼是合理的联合治疗方案。由于目前肝癌治疗受到耐药性的严重限制，这些结果应促使开展旨在改善晚期肝癌治疗反应的临床研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a232/8782451/5cde4b63208d/sciadv.abh2635-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a232/8782451/5cde4b63208d/sciadv.abh2635-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a232/8782451/d6f1a95b71a9/sciadv.abh2635-f1.jpg
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2
Hepatocellular carcinoma.肝细胞癌。
Nat Rev Dis Primers. 2021 Jan 21;7(1):6. doi: 10.1038/s41572-020-00240-3.
3
Atezolizumab plus bevacizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a cost-effectiveness analysis.阿替利珠单抗联合贝伐单抗与索拉非尼作为不可切除肝细胞癌一线治疗的成本效益分析
器官异种组学：一个用于患者来源类器官和异种移植的综合蛋白质组知识库。
Nucleic Acids Res. 2025 Jan 6;53(D1):D504-D515. doi: 10.1093/nar/gkae861.
4
Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.线粒体代谢：肝细胞癌治疗中一个不断变化的靶点。
J Cell Physiol. 2025 Jan;240(1):e31441. doi: 10.1002/jcp.31441. Epub 2024 Sep 26.
5
Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis.硫辛酸通过 AMPK-p53 轴减少肝癌细胞的迁移和侵袭。
Sci Rep. 2024 Sep 11;14(1):21275. doi: 10.1038/s41598-024-72309-y.
6
Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes.抑制神经元 CDK9/p53/VDAC 信号转导可提供能量代谢支持并改善卒中后神经精神结局。
Cell Mol Life Sci. 2024 Sep 5;81(1):384. doi: 10.1007/s00018-024-05428-4.
7
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Cell Oncol (Dordr). 2025 Feb;48(1):161-182. doi: 10.1007/s13402-024-00966-2. Epub 2024 Jul 11.
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10
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