College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang 110001, Liaoning Province, China.
Department of Ultrasound Medicine, Liaoning Cancer Hospital, Shenyang 110001, Liaoning Province, China.
Int J Biol Sci. 2024 Aug 5;20(11):4190-4208. doi: 10.7150/ijbs.97720. eCollection 2024.
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 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.
生长抑制剂 5（ING5）已被报道参与癌症的恶性进展。熊果酸（UA）已显示出显著的抗肿瘤作用。然而，其关于肝细胞癌（HCC）中 ING5 的抗肿瘤机制尚不清楚。在此，我们发现 UA 可显著抑制 HCC 细胞的增殖、抗凋亡、迁移和侵袭。此外，UA 处理的 HCC 细胞中 ING5 的表达呈浓度和时间依赖性明显下调。此外，ING5 在 HCC 细胞中发挥致癌作用得到了证实。进一步的研究表明，UA 通过抑制 ING5 介导的 PI3K/Akt 通路激活对 HCC 发挥抗肿瘤作用。值得注意的是，UA 还可以通过抑制 ING5-ACC1/ACLY-脂滴（LDs）轴来逆转 HCC 细胞对索拉非尼的耐药性。UA 通过降低 SRF 和 YY1 的表达以及减少 SRF-YY1 复合物的形成来抑制 ING5 的转录和下调其表达。由于 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，因此在 Alb/JCPyV T 抗原小鼠中进行了实验。UA 通过抑制 ING5 介导的 PI3K/Akt 信号通路抑制 JCPyV T 抗原诱导的自发性 HCC。这些发现表明，UA 通过靶向 ING5 具有抑制肝细胞癌发生和逆转 HCC 细胞索拉非尼耐药的双重抗肿瘤功能，可为 HCC 提供一种潜在的治疗策略。
