Moscatilin Inhibits Metastatic Behavior of Human Hepatocellular Carcinoma Cells: A Crucial Role of uPA Suppression via Akt/NF-κB-Dependent Pathway.

Chen-Lin Yu,Chih-Wen Chi,Po-Chuan Wang,Wei-Cheng Chen,Shih-Chia Liu,Shih-Wei Wang,Ching-Hu Chung,Meng-Shih Weng,Chien-Chih Chen,Kai-Ting Chien,Chia-Wen Huang,An-Chi Tsai

doi:10.3390/ijms22062930

Abstract

Hepatocellular carcinoma (HCC) frequently shows early invasion into blood vessels as well as intrahepatic metastasis. Innovations of novel small-molecule agents to block HCC invasion and subsequent metastasis are urgently needed. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, orchid Dendrobium loddigesii. Although moscatilin has been reported to suppress tumor angiogenesis and growth, the anti-metastatic property of moscatilin has not been elucidated. The present results revealed that moscatilin inhibited metastatic behavior of HCC cells without cytotoxic fashion in highly invasive human HCC cell lines. Furthermore, moscatilin significantly suppressed the activity of urokinase plasminogen activator (uPA), but not matrix metalloproteinase (MMP)-2 and MMP-9. Interestingly, moscatilin-suppressed uPA activity was through down-regulation the protein level of uPA, and did not impair the uPA receptor and uPA inhibitory molecule (PAI-1) expressions. Meanwhile, the mRNA expression of uPA was inhibited via moscatilin in a concentration-dependent manner. In addition, the expression of phosphorylated Akt, rather than ERK1/2, was inhibited by moscatilin treatment. The expression of phosphor-IκBα, and -p65, as well as κB-luciferase activity were also repressed after moscatilin treatment. Transfection of constitutively active Akt (Myr-Akt) obviously restored the moscatilin-inhibited the activation of NF-κB and uPA, and cancer invasion in HCC cells. Taken together, these results suggest that moscatilin impedes HCC invasion and uPA expression through the Akt/NF-κB signaling pathway. Moscatilin might serve as a potential anti-metastatic agent against the disease progression of human HCC.

Highlights

IntroductionHepatocellular carcinoma (HCC) is the most common malignancy of liver cancer and is the secondary cause of cancer-related death in the world, especially in Asian countries [1,2]
Hepatocellular carcinoma (HCC) is the most common malignancy of liver cancer and is the secondary cause of cancer-related death in the world, especially in Asian countries [1,2].Generally, the risk factors of HCC are region, gender, and etiology
Our results revealed that moscatilin suppresses urokinase plasminogen activator (uPA)-mediated HCC metastasis via inhibiting the Akt-dependent Nuclear factor-κB (NF-κB) signaling pathway

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common malignancy of liver cancer and is the secondary cause of cancer-related death in the world, especially in Asian countries [1,2]. The risk factors of HCC are region, gender, and etiology. The male population, Asian people, and those infected by hepatitis virus B or C (HBV or HCV) are at a high-risk of HCC [3]. Diagnosis and surgical resection are the better strategy for HCC therapy, which increase overall and disease-free survival rate [4]. The high potential of recurrences and distant metastasis enlarge the mortality rate of HCC. Developing a novel strategy for HCC treatment is necessary

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Results

Conclusion