Cholesterol suppresses AMFR-mediated PDL1 ubiquitination and degradation in HCC.

IF 3.5 2区 生物学 Q3 CELL BIOLOGY Molecular and Cellular Biochemistry Pub Date : 2025-03-01 Epub Date: 2024-09-04 DOI:10.1007/s11010-024-05106-w
Wei-Qing Shao, Yi-Tong Li, Xu Zhou, Sheng-Guo Zhang, Ming-Hao Fan, Dong Zhang, Zhen-Mei Chen, Chen-He Yi, Sheng-Hao Wang, Wen-Wei Zhu, Ming Lu, Ji-Song Chen, Jing Lin, Yu Zhou
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Abstract

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

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胆固醇可抑制 HCC 中 AMFR 介导的 PDL1 泛素化和降解。
蛋白酶体或溶酶体的降解正在成为程序性死亡配体1(PDL1)表达的主要决定因素,而PDL1的表达会影响各种恶性肿瘤的免疫疗法的疗效。细胞内胆固醇在维持膜受体的表达方面起着核心作用;然而,胆固醇对癌细胞中 PDL1 表达的具体影响仍鲜为人知。研究人员利用胆固醇饥饿和刺激来调节细胞胆固醇水平。免疫组化和 Western 印迹技术用于分析样本和细胞中的蛋白质水平。定量实时 PCR、共免疫沉淀和共聚焦分析用于机理研究。为了在体内验证这些结果,我们构建了一个异种移植肿瘤模型。我们的研究结果表明,胆固醇抑制了肝细胞癌(HCC)细胞中 PDL1 的泛素化和降解。进一步的机理研究发现,自分泌运动因子受体(AMFR)是介导PDL1泛素化和降解的E3连接酶,而PDL1的泛素化和降解受胆固醇/p38丝裂原活化蛋白激酶轴的调控。此外,使用他汀类药物降低胆固醇水平可提高体内程序性死亡1(PD1)抑制的疗效。我们的研究结果表明,胆固醇是抑制AMFR介导的PDL1泛素化和降解的信号,并提示他汀类药物降低胆固醇可能是提高HCC中PD1抑制效率的一种有前景的组合策略。
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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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