Corosolic Acid Inhibits Hepatocellular Carcinoma Cell Migration by Targeting the VEGFR2/Src/FAK Pathway.

Chung-Yu Ku,Ying-Ren Wang,Shao-Chun Lu,Hsuan-Yuan Lin,Jung-Yaw Lin,Yu-Jia Chang

doi:10.1371/journal.pone.0126725

Chung-Yu Ku, Ying-Ren Wang + Show 4 more

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https://doi.org/10.1371/journal.pone.0126725

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Abstract

Inhibition of VEGFR2 activity has been proposed as an important strategy for the clinical treatment of hepatocellular carcinoma (HCC). In this study, we identified corosolic acid (CA), which exists in the root of Actinidia chinensis, as having a significant anti-cancer effect on HCC cells. We found that CA inhibits VEGFR2 kinase activity by directly interacting with the ATP binding pocket. CA down-regulates the VEGFR2/Src/FAK/cdc42 axis, subsequently decreasing F-actin formation and migratory activity in vitro. In an in vivo model, CA exhibited an effective dose (5 mg/kg/day) on tumor growth. We further demonstrate that CA has a synergistic effect with sorafenib within a wide range of concentrations. In conclusion, this research elucidates the effects and molecular mechanism for CA on HCC cells and suggests that CA could be a therapeutic or adjuvant strategy for patients with aggressive HCC.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of death from cancer [1]
We showed that corosolic acid (CA), which was found in the water extracts of Actinidia chinensis, exhibited significant anti-cancer effects in HCC cells by decreasing HCC cell migration without cytotoxicity
The results indicate that CA has a relatively higher inhibitory effect on Huh7 cell migration than cell viability. (IC50 cytotoxicity/ IC50 migration = 20)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of death from cancer [1]. Previous studies have implicated emerging pathways in HCC, such as HGF/MET, Wnt/β-catenin, and VEGF/ VEGFR; these pathways could serve as novel molecular targets for developing anti-HCC therapies [3,4,5]. Cancer cell migration is a critical process in tumor development and metastasis [6, 7], and anti-migration therapy is considered to be an important approach for HCC treatment. VEGF receptor signaling, VEGFR2 (KDR), has been implicated in HCC migration. Previous studies have shown that VEGFR knockdown reduces HCC cell migration [11]. Small molecule inhibition of VEGFR2 reduces cancer cell migration [12, 13] and tumor growth in vivo [14,15,16]

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