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乳酸化驱动的IGF2BP3介导的丝氨酸代谢重编程和RNA m6A修饰促进肝癌对乐伐替尼的耐药性

Lactylation-Driven IGF2BP3-Mediated Serine Metabolism Reprogramming and RNA m6A-Modification Promotes Lenvatinib Resistance in HCC.

作者信息

Lu Yuanxiang, Zhu Jinghan, Zhang Yuxin, Li Wentao, Xiong Yixiao, Fan Yunhui, Wu Yang, Zhao Jianping, Shang Changzhen, Liang Huifang, Zhang Wanguang

机构信息

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.

Department of Breast Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, 450003, China.

出版信息

Adv Sci (Weinh). 2024 Dec;11(46):e2401399. doi: 10.1002/advs.202401399. Epub 2024 Oct 25.

DOI:10.1002/advs.202401399
PMID:39450426
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11633555/
Abstract

Acquired resistance remains a bottleneck for molecular-targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib-resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S-adenosylmethionine (SAM), for N6-methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3-PCK2-SAM-m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2-DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC.

摘要

获得性耐药仍然是晚期肝细胞癌（HCC）分子靶向治疗的一个瓶颈。代谢适应和表观遗传重塑被认为是癌症的标志，可能导致获得性耐药。在各种乐伐替尼耐药模型中，糖酵解增加导致乳酸积累以及IGF2BP3的赖氨酸乳酰化。这种乳酰化对于捕获PCK2和NRF2 mRNA至关重要，从而增强它们的表达。这一过程重新编程丝氨酸代谢并加强抗氧化防御系统。此外，改变的丝氨酸代谢增加了甲基化底物（如S-腺苷甲硫氨酸（SAM））的可用性，用于PCK2和NRF2 mRNA的N6-甲基腺苷（m6A）甲基化。乳酰化的IGF2BP3-PCK2-SAM-m6A环维持PCK2和NRF2的高水平，增强抗氧化系统并促进HCC中的乐伐替尼耐药。用携带靶向IGF2BP3的siRNA的脂质体或糖酵解抑制剂2-DG进行治疗可在体内恢复乐伐替尼敏感性。这些发现突出了代谢重编程与表观遗传调控之间的联系，并表明靶向代谢途径可能为克服HCC中的乐伐替尼耐药提供新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/3e07bfd9e405/ADVS-11-2401399-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/3e07bfd9e405/ADVS-11-2401399-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/2a4608a0bdef/ADVS-11-2401399-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/2322db6d439b/ADVS-11-2401399-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/f379658ed9f5/ADVS-11-2401399-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/23bc0b0edf77/ADVS-11-2401399-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/fdbc63be6401/ADVS-11-2401399-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/1c8f54bf438e/ADVS-11-2401399-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07a9/11633555/3e07bfd9e405/ADVS-11-2401399-g005.jpg

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