Koumine Promotes ROS Production to Suppress Hepatocellular Carcinoma Cell Proliferation Via NF-κB and ERK/p38 MAPK Signaling.

Yuan Yuan,Chen Chen,Wu Wu,Sun Sun,Liang Liang,Li Li,Yi Yi

doi:10.3390/biom9100559

Abstract

In the past decades, hepatocellular carcinoma (HCC) has been receiving increased attention due to rising morbidity and mortality in both developing and developed countries. Koumine, one of the significant alkaloidal constituents of Gelsemium elegans Benth., has been regarded as a promising anti-inflammation, anxiolytic, and analgesic agent, as well as an anti-tumor agent. In the present study, we attempted to provide a novel mechanism by which koumine suppresses HCC cell proliferation. We demonstrated that koumine might suppress the proliferation of HCC cells and promote apoptosis in HCC cells dose-dependently. Under koumine treatment, the mitochondria membrane potential was significantly decreased while reactive oxygen species (ROS) production was increased in HCC cells; in the meantime, the phosphorylation of ERK, p38, p65, and IκBα could all be inhibited by koumine treatment dose-dependently. More importantly, the effects of koumine upon mitochondria membrane potential, ROS production, and the phosphorylation of ERK, p38, p65, and IκBα could be significantly reversed by ROS inhibitor, indicating that koumine affects HCC cell fate and ERK/p38 MAPK and NF-κB signaling activity through producing excess ROS. In conclusion, koumine could inhibit the proliferation of HCC cells and promote apoptosis in HCC cells; NF-κB and ERK/p38 MAPK pathways could contribute to koumine functions in a ROS-dependent manner.

Highlights

Hepatocellular carcinoma (HCC) is the most commonly seen primary liver cancer; it accounts for 85% of the liver cancers [1]
As revealed by the MTT assays, the cell viability of hepatocellular carcinoma (HCC) cells were significantly inhibited by koumine dose-dependently (Figure 1A)
Bax, were significantly increased, while Caspase3 and Bcl2 protein levels were decreased by koumine dose-dependently (Figure 1C)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most commonly seen primary liver cancer; it accounts for 85% of the liver cancers [1]. Other forms include cholangiocarcinoma, which begins with cells surrounding the bile duct, angiosarcoma (or hemangiosarcoma), and hepatoblastoma. Occurring in the developing world [2,3], HCC has been receiving increased attention due to rising morbidity and mortality in many countries for the past few years [4,5,6]. Environmental factors or cellular mitochondrial dysfunction lead to the production of reactive oxygen species (ROS), resulting in sustained oxidative stress, which is related to liver carcinogenesis according to recent studies [7]. Improved ROS can induce oxidative stress and provide an environment that is potentially toxic to cells.

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Results

Discussion

Conclusion