The Antitumor and Sorafenib-resistant Reversal Effects of Ursolic Acid on Hepatocellular Carcinoma via Targeting ING5.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-08-05 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.97720
Yin-Jie Fan, Fu-Zhi Pan, Zheng-Guo Cui, Hua-Chuan Zheng
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引用次数: 0

Abstract

Inhibitor of growth 5 (ING5) has been reported to be involved in the malignant progression of cancers. Ursolic acid (UA) has shown remarkable antitumor effects. However, its antitumor mechanisms regarding of ING5 in hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UA significantly suppressed the proliferation, anti-apoptosis, migration and invasion of HCC cells. In addition, ING5 expression in HCC cells treated with UA was obviously downregulated in a concentration- and time-dependent manner. Additionally, the pro-oncogenic role of ING5 was confirmed in HCC cells. Further investigation revealed that UA exerted antitumor effects on HCC by inhibiting ING5-mediated activation of PI3K/Akt pathway. Notably, UA could also reverse sorafenib resistance of HCC cells by suppressing the ING5-ACC1/ACLY-lipid droplets (LDs) axis. UA abrogated ING5 transcription and downregulated its expression by reducing SRF and YY1 expression and the SRF-YY1 complex formation. Alb/JCPyV T antigen mice were used for in vivo experiments since T antigen upregulated ING5 expression by inhibiting the ubiquitin-mediated degradation and promoting the T antigen-SRF-YY1-ING5 complex-associated transcription. UA suppressed JCPyV T antigen-induced spontaneous HCC through inhibiting ING5-mediated PI3K/Akt signaling pathway. These findings suggest that UA has the dual antitumoral functions of inhibiting hepatocellular carcinogenesis and reversing sorafenib resistance of HCC cells through targeting ING5, which could serve as a potential therapeutic strategy for HCC.

熊果酸通过靶向 ING5 对肝细胞癌的抗肿瘤和索拉非尼耐药逆转作用
据报道,生长抑素 5(ING5)与癌症的恶性发展有关。熊果酸(UA)具有显著的抗肿瘤作用。然而,它对肝细胞癌(HCC)中ING5的抗肿瘤机制仍不清楚。在本文中,我们发现 UA 能显著抑制 HCC 细胞的增殖、抗凋亡、迁移和侵袭。此外,用 UA 处理的 HCC 细胞中 ING5 的表达明显下调,且呈浓度和时间依赖性。此外,还证实了 ING5 在 HCC 细胞中的促癌作用。进一步研究发现,UA 通过抑制 ING5 介导的 PI3K/Akt 通路活化对 HCC 发挥抗肿瘤作用。值得注意的是,UA还能通过抑制ING5-ACC1/ACLY-脂滴(LDs)轴来逆转HCC细胞对索拉非尼的耐药性。UA 可通过减少 SRF 和 YY1 的表达以及 SRF-YY1 复合物的形成来抑制 ING5 的转录并下调其表达。Alb/JCPyV T 抗原小鼠被用于体内实验,因为 T 抗原通过抑制泛素介导的降解和促进 T 抗原-SRF-YY1-ING5 复合物相关转录来上调 ING5 的表达。UA 通过抑制 ING5 介导的 PI3K/Akt 信号通路,抑制了 JCPyV T 抗原诱导的自发性 HCC。这些研究结果表明,UA通过靶向ING5具有抑制肝细胞癌变和逆转HCC细胞索拉非尼耐药的双重抗肿瘤功能,可作为HCC的一种潜在治疗策略。
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
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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