Aurora-A inhibits hepatocellular carcinoma cell ferroptosis to mediate immune escape by disrupting phosphatidylethanolamine biosynthesis.

IF 2.9 3区医学 Q2 ONCOLOGY

American journal of cancer research Pub Date : 2025-08-25 eCollection Date: 2025-01-01 DOI:10.62347/JTQO8098

Lei Fan, Yiqian Liu, Yucheng Cai, Xinnan Sun, Jiaxuan Li, Yiyang Xu, Changchun Sun, Shiyun Cui

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引用次数: 0

Abstract

This study aims to explore Aurora-A's role in regulating immune escape of hepatocellular carcinoma (HCC). We performed non-targeted metabolomics analysis and analyzed the impact of Aurora-A inhibitor Alisertib on anti-PD-1 therapy efficacy on xenograft tumors and co-culture models of CD8⁺ T cells and HCC cells. We determined reactive oxygen species (ROS) and malondialdehyde (MDA) production in HCC cells to evaluate lipid peroxidation. Confocal images of endoplasmic reticulum (ER) and mitochondria in HCC cells were taken to assess the role of Aurora-A and dynamin-related protein 1 (Drp-1) on mitochondria-associated endoplasmic reticulum membranes (MAMs) formation. The results showed that Aurora-A was upregulated in HCC cells and its knockdown significantly augmented phosphatidylethanolamine (PE) production while having no effect on phosphatidylserine decarboxylase (PSD). Further, Aurora-A inhibitor Alisertib enhanced the sensibility of HCC cells to anti-PD-1 therapy and CD45⁺CD8⁺ T cell infiltration in HCC tumors. To conclude, our work revealed that Aurora-A dysregulated PS/PE metabolism via facilitating Drp1-Ser616 phosphorylation to disrupt MAMs formation, resulting in suppressed ferroptosis in HCC cells to reduce their sensitivity to anti-PD-1.

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Aurora-A通过破坏磷脂酰乙醇胺生物合成抑制肝癌细胞铁下垂介导免疫逃逸。

本研究旨在探讨Aurora-A在肝细胞癌（HCC）免疫逃逸调控中的作用。我们进行了非靶向代谢组学分析，分析了Aurora-A抑制剂Alisertib对异种移植肿瘤抗pd -1治疗效果的影响以及CD8+ T细胞和HCC细胞共培养模型。我们测定了肝癌细胞中活性氧（ROS）和丙二醛（MDA）的产生，以评估脂质过氧化。采用肝癌细胞内质网（ER）和线粒体的共聚焦图像来评估Aurora-A和动力蛋白相关蛋白1 （Drp-1）在线粒体相关内质网膜（MAMs）形成中的作用。结果表明，Aurora-A在HCC细胞中表达上调，其敲低显著增加了磷脂酰乙醇胺（PE）的产生，而对磷脂酰丝氨酸脱羧酶（PSD）没有影响。此外，Aurora-A抑制剂Alisertib增强了HCC细胞对抗pd -1治疗的敏感性和HCC肿瘤中CD45+CD8+ T细胞浸润的敏感性。总之，我们的研究表明，Aurora-A通过促进Drp1-Ser616磷酸化来破坏MAMs的形成，从而失调PS/PE代谢，从而抑制HCC细胞中的铁凋亡，降低其对抗pd -1的敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

American journal of cancer research ONCOLOGY-

自引率

3.80%

发文量

263

期刊介绍： The American Journal of Cancer Research (AJCR) (ISSN 2156-6976), is an independent open access, online only journal to facilitate rapid dissemination of novel discoveries in basic science and treatment of cancer. It was founded by a group of scientists for cancer research and clinical academic oncologists from around the world, who are devoted to the promotion and advancement of our understanding of the cancer and its treatment. The scope of AJCR is intended to encompass that of multi-disciplinary researchers from any scientific discipline where the primary focus of the research is to increase and integrate knowledge about etiology and molecular mechanisms of carcinogenesis with the ultimate aim of advancing the cure and prevention of this increasingly devastating disease. To achieve these aims AJCR will publish review articles, original articles and new techniques in cancer research and therapy. It will also publish hypothesis, case reports and letter to the editor. Unlike most other open access online journals, AJCR will keep most of the traditional features of paper print that we are all familiar with, such as continuous volume, issue numbers, as well as continuous page numbers to retain our comfortable familiarity towards an academic journal.