Chen Fang
Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, 610072, China.
Biochem Biophys Res Commun. 2024 Jun 18;712-713:149899. doi: 10.1016/j.bbrc.2024.149899. Epub 2024 Apr 5.
Quercetin, a naturally occurring flavonoid, has been investigated for its potential anti-cancer effects in various types of cancer, including hepatocellular carcinoma (HCC). However, its suppressing effect on reactive oxygen species (ROS) production might limited its anti-cancer effects. In this study, we aimed to explore the interplay among quercetin, mitochondrial dynamics and mitophagy and whether mitophagy-inhibition synergistically enhances the anti-tumor effects of quercetin. Huh7 and Hep3B cells were utilized for in vitro and in vivo studies. Results showed that quercetin treatment significantly increased the expression of mitochondrial fusion genes (MFN1 and MFN2) and decreased the expression of fission genes (DRP1 and FIS1) in Huh7 and Hep3B cells, leading to a more fused and elongated mitochondrial network. Quercetin upregulated the expression of key mitophagy regulators, PINK1 and PARK2, and enhanced the colocalization of mitochondria with lysosomes, indicating increased mitophagy. Knockdown of PINK1, PARK2, or SIRT1 attenuated quercetin-induced mitophagy and reduction of intracellular ROS levels. Quercetin treatment upregulates SIRT1 expression, which subsequently enhances PINK1 and PARK2 expression in Huh7 and Hep3B cells. In vivo experiments using Hep3B xenograft models revealed that the combination of quercetin with the mitophagy inhibitor hydroxychloroquine or SIRT1 knockdown significantly enhanced the anticancer effects of quercetin, as evidenced by reduced tumor size and weight, increased necrosis and apoptosis, and decreased proliferation in tumor tissues. These findings suggest that quercetin-induced mitochondrial fusion and Pink1/Parkin-dependent mitophagy may negatively influence its anti-cancer effects in HCC. Targeting mitophagy may enhance the therapeutic potential of quercetin in HCC treatment.
槲皮素是一种天然存在的类黄酮，已针对其在包括肝细胞癌（HCC）在内的各种癌症中的潜在抗癌作用进行了研究。然而，其对活性氧（ROS）产生的抑制作用可能会限制其抗癌效果。在本研究中，我们旨在探讨槲皮素、线粒体动力学和线粒体自噬之间的相互作用，以及线粒体自噬抑制是否能协同增强槲皮素的抗肿瘤作用。使用Huh7和Hep3B细胞进行体外和体内研究。结果表明，槲皮素处理显著增加了Huh7和Hep3B细胞中线粒体融合基因（MFN1和MFN2）的表达，并降低了裂变基因（DRP1和FIS1）的表达，导致线粒体网络更加融合和延长。槲皮素上调了关键线粒体自噬调节因子PINK1和PARK2的表达，并增强了线粒体与溶酶体的共定位，表明线粒体自噬增加。敲低PINK1、PARK2或SIRT1可减弱槲皮素诱导的线粒体自噬和细胞内ROS水平的降低。槲皮素处理上调了SIRT1的表达，随后增强了Huh7和Hep3B细胞中PINK1和PARK2的表达。使用Hep3B异种移植模型的体内实验表明，槲皮素与线粒体自噬抑制剂羟氯喹或SIRT1敲低的联合使用显著增强了槲皮素的抗癌作用，肿瘤大小和重量减小、坏死和凋亡增加以及肿瘤组织增殖减少证明了这一点。这些发现表明，槲皮素诱导的线粒体融合和Pink1/Parkin依赖性线粒体自噬可能对其在HCC中的抗癌作用产生负面影响。靶向线粒体自噬可能会增强槲皮素在HCC治疗中的治疗潜力。
