Fan Shao-hua, Wang Yan-yan, Lu Jun, Zheng Yuan-lin, Wu Dong-mei, Li Meng-qiu, Hu Bin, Zhang Zi-feng, Cheng Wei, Shan Qun
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, China.
Department of Function Examination, The First People's Hospital of Xuzhou, Jiangsu, China.
PLoS One. 2014 Feb 26;9(2):e89961. doi: 10.1371/journal.pone.0089961. eCollection 2014.
The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.
炎性小体是一种多蛋白复合物，激活后可调节半胱天冬酶-1的激活和白细胞介素-1β的分泌。炎性小体的激活由对刺激作出反应的NLR蛋白介导。在NLR中，NLRP3能感知最广泛的刺激。NLRP3炎性小体在多种癌症类型的发展中起重要作用。然而，NLRP3炎性小体在肝细胞癌（HCC）过程中是否起重要作用仍不清楚。在此，研究了从药用植物秦艽中分离出的天然黄酮木犀草苷对肝癌细胞的抗癌作用及其潜在机制。木犀草苷在体外和体内均显著抑制肝癌细胞的增殖。活细胞成像和Transwell实验表明，与对照细胞相比，用木犀草苷处理的肝癌细胞的迁移和侵袭能力显著受到抑制。在雄性BALB/c-nu/nu小鼠肺转移模型中也观察到了木犀草苷对转移的抑制作用。进一步研究表明，木犀草苷可显著降低细胞内活性氧（ROS）的积累。木犀草苷诱导的ROS水平降低伴随着NLRP3炎性小体表达的降低，导致半胱天冬酶-1的蛋白水解切割减少。木犀草苷使半胱天冬酶-1失活，从而抑制白细胞介素-1β。因此，木犀草苷通过抑制NLRP3炎性小体对肝癌细胞的增殖、侵袭和转移发挥抑制作用。我们的结果表明，木犀草苷不仅可以作为肝癌的辅助治疗药物，而且在控制和预防转移性肝癌方面可能是一种潜在的治疗剂。
