Chen Jingyi, Zhao Fangxin, Yang Hongxin, Wen Jianxun, Tang Ying, Wan Fang, Zhang Xuan, Wu Jianqiang
College of Basic Medicine, Inner Mongolia Medical University Hohhot, Inner Mongolia, China.
School of Life Sciences, Inner Mongolia University Hohhot, Inner Mongolia, China.
Am J Cancer Res. 2022 Jul 15;12(7):3357-3372. eCollection 2022.
Hepatocellular carcinoma (HCC) is the fifth most common malignancies with limited curative options and poor prognosis. Gentian violet (GV) has recently been found to have anti-tumor properties with promising clinical applications. However, its anti-tumor effect and the underlying functional mechanisms in HCC have not been investigated. In this study, we found that GV induced ferroptosis and apoptosis, inhibited cell proliferation, migration and invasion in a dose-dependent manner , and significantly attenuated the growth of HCC . Both ferroptosis inhibitor Ferrostain-1 (Fer-1) and apoptosis inhibitor Z-VAD-KFM (Z-VAD) partially attenuated GV-induced growth-inhibitory effects, while combined treatment of Fer-1 and Z-VAD completely abolished GV's activities. Increased levels of intracellular reactive oxygen species (ROS) were detected after GV treatment. Interestingly, GV elevated the expression levels of both p53 and its negative regulator MDM2, which was dependent on the expression of the dehydrogenase/reductase protein Hep27. Simultaneously silencing both the MDM2 and p53 genes by siRNAs abolished ROS production and partially rescued the cell death induced by GV treatment. Our data demonstrate a GV-Hep27-MDM2-p53 signaling cascade that regulates ferroptosis and apoptosis. Furthermore, our findings provide insights into understanding the anti-tumor function of GV and present the basis of new therapeutic strategies for the treatment of HCC.
肝细胞癌（HCC）是第五大常见恶性肿瘤，治疗选择有限且预后较差。最近发现龙胆紫（GV）具有抗肿瘤特性，具有广阔的临床应用前景。然而，其在肝癌中的抗肿瘤作用及潜在功能机制尚未得到研究。在本研究中，我们发现GV以剂量依赖性方式诱导铁死亡和凋亡，抑制细胞增殖、迁移和侵袭，并显著抑制肝癌生长。铁死亡抑制剂Ferrostain-1（Fer-1）和凋亡抑制剂Z-VAD-KFM（Z-VAD）均部分减弱了GV诱导的生长抑制作用，而Fer-1和Z-VAD联合处理则完全消除了GV的活性。GV处理后检测到细胞内活性氧（ROS）水平升高。有趣的是，GV提高了p53及其负调节因子MDM2的表达水平，这依赖于脱氢酶/还原酶蛋白Hep27的表达。通过小干扰RNA（siRNA）同时沉默MDM2和p53基因可消除ROS产生，并部分挽救GV处理诱导的细胞死亡。我们的数据证明了一种调节铁死亡和凋亡的GV-Hep27-MDM2-p53信号级联反应。此外，我们的研究结果为理解GV的抗肿瘤功能提供了见解，并为肝癌治疗新策略奠定了基础。
