2-Hydroxy-3-Methylanthraquinone Suppresses Hepatocellular Carcinoma Progression by Blocking Annexin A5-Mediated Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling

IF 3.2 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Min Luo, Juanmei Mo, Chaoyuan Huang, Yan Mao, Hongzhi Wang, Xiaochen Wang
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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC), the most common subtype of primary liver cancer, remains a major cause of cancer-related mortality worldwide. Although 2-hydroxy-3-methylanthraquinone (HMA), a natural anthraquinone compound, has demonstrated antitumor activity in various malignancies, its specific role and underlying mechanisms in HCC are not fully understood. This study aimed to evaluate the antitumor effects and molecular mechanisms of HMA in HCC. Human HCC cell lines were treated with HMA, and cell proliferation and apoptosis were assessed using Cell Counting Kit-8 and flow cytometry assays, respectively. A heterotopic xenograft tumor model was established in nude mice to evaluate in vivo tumor growth and weight. Immunohistochemical staining for Ki67 and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to assess tumor cell proliferation and apoptosis. Network pharmacology analysis was conducted to predict potential targets of HMA in HCC. Quantitative real-time polymerase chain reaction and Western blotting were used to evaluate mRNA and protein expression levels. Cell migration and invasion were assessed using wound healing and transwell assays. Our data revealed that HMA significantly suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in both HCC cells and tumor tissues. Mechanistically, HMA downregulated Annexin A5 (ANXA5) expression and inhibited activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Silencing of ANXA5 replicated the inhibitory effects of HMA and further enhanced its pro-apoptotic and anti-invasive activities. Conversely, overexpression of ANXA5 restored PI3K/AKT signaling activity and reversed the inhibitory effects of HMA on HepG2 cell proliferation, migration, and invasion. These reversal effects were abolished by treatment with LY294002, a selective PI3K inhibitor. In summary, HMA suppresses the progression of HCC by targeting ANXA5 and inhibiting the PI3K/AKT signaling pathway, highlighting its potential as a novel therapeutic agent for HCC.

2-羟基-3-甲基蒽醌通过阻断膜联蛋白a5介导的磷脂酰肌醇3-激酶/蛋白激酶B信号传导抑制肝癌进展
肝细胞癌(HCC)是原发性肝癌最常见的亚型,仍然是世界范围内癌症相关死亡的主要原因。虽然2-羟基-3-甲基蒽醌(HMA)是一种天然蒽醌类化合物,在多种恶性肿瘤中显示出抗肿瘤活性,但其在HCC中的具体作用和潜在机制尚不完全清楚。本研究旨在探讨HMA在HCC中的抗肿瘤作用及其分子机制。用HMA处理人肝癌细胞系,分别用细胞计数试剂盒-8和流式细胞术检测细胞增殖和细胞凋亡。建立裸鼠异位异种移植瘤模型,观察肿瘤在体内的生长和重量变化。免疫组织化学染色Ki67和末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)法评估肿瘤细胞的增殖和凋亡。通过网络药理学分析预测HCC中HMA的潜在靶点。采用实时定量聚合酶链反应和Western blotting检测mRNA和蛋白表达水平。通过伤口愈合和transwell试验评估细胞迁移和侵袭。我们的数据显示,HMA在HCC细胞和肿瘤组织中均能显著抑制细胞增殖、诱导细胞凋亡、抑制迁移和侵袭。机制上,HMA下调了Annexin A5 (ANXA5)的表达,抑制了磷脂酰肌醇3-激酶/蛋白激酶B (PI3K/AKT)信号通路的激活。沉默ANXA5可复制HMA的抑制作用,并进一步增强其促凋亡和抗侵袭活性。相反,过表达ANXA5可恢复PI3K/AKT信号活性,逆转HMA对HepG2细胞增殖、迁移和侵袭的抑制作用。这些逆转作用被LY294002(一种选择性PI3K抑制剂)所消除。综上所述,HMA通过靶向ANXA5和抑制PI3K/AKT信号通路抑制HCC的进展,突出了其作为HCC新型治疗剂的潜力。
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
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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