Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-induced death worldwide, and patients have a very poor prognosis [1,2]
Luteoloside Inhibits the Proliferation of HCC Cells in vitro We first determined whether luteoloside inhibits the proliferation of human HCC cells
The results suggest that luteoloside has promising antihepatoma activity
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-induced death worldwide, and patients have a very poor prognosis [1,2]. HCC is treated by surgical resection or liver transplantation, which curative options for the patients when the disease is diagnosed at an early stage. Approximately 70% of patients are inoperable because of tumor metastasis [3]. The current therapeutic options for HCC are not very effective because it is resistant to chemotherapy. Many anticancer drugs have toxicity and side effects for the patients. Novel therapeutic strategies are needed to decrease the incidence and severity associated with this cancer [4]. There is a pressing need for new therapeutic drugs with increased efficacy and decreased toxicity
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