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Toxicol In Vitro. 2014 Aug;28(5):751-8. doi: 10.1016/j.tiv.2014.02.015. Epub 2014 Mar 12.

18β-Glycyrrhetinic acid suppresses TNF-α induced matrix metalloproteinase-9 and vascular endothelial growth factor by suppressing the Akt-dependent NF-κB pathway.

Author information

  • 1Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea.
  • 2Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-054, Republic of Korea.
  • 3School of Medicine, Jeju National University, Jeju-si 690-756, Republic of Korea.
  • 4Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea. Electronic address: immunkim@jejunu.ac.kr.

Abstract

Little is known about the molecular mechanism through which 18β-glycyrrhetinic acid (GA) inhibits metastasis and invasion of cancer cells. Therefore, this study aimed to investigate the effects of GA on the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in various types of cancer cells. We found that treatment with GA reduces tumor necrosis factor-α (TNF-α)-induced Matrigel invasion with few cytotoxic effects. Our findings also showed that MMP-9 and VEGF expression increases in response to TNF-α; however, GA reverses their expression. In addition, GA inhibited inhibitory factor kappa B degradation, sustained nuclear factor-kappa B (NF-κB) subunits, p65 and p50, in the cytosol compartments, and consequently suppressed the TNF-α-induced DNA-binding activity and luciferase activity of NF-κB. Specific NF-κB inhibitors, pyrrolidine dithiocarbamate, MG132, and PS-1145, also attenuated TNF-α-mediated MMP-9 and VEGF expression as well as activity by suppressing their regulatory genes. Furthermore, phosphorylation of TNF-α-induced phosphatidyl-inositol 3 kinase (PI3K)/Akt was significantly downregulated in the presence of GA accompanying with the inhibition of NF-κB activity, and as presumed, the specific PI3K/Akt inhibitor LY294002 significantly decreased MMP-9 and VEGF expression as well as activity. These results suggest that GA operates as a potential anti-invasive agent by downregulating MMP-9 and VEGF via inhibition of PI3K/Akt-dependent NF-κB activity. Taken together, GA might be an effective anti-invasive agent by suppressing PI3K/Akt-mediated NF-κB activity.

KEYWORDS:

18β-Glycyrrhetinic acid; Akt; Matrix metalloproteinase; Nuclear factor-kappa B; Phosphatidyl-inositol 3 kinase; Vascular endothelial growth factor

PMID:
24613819
DOI:
10.1016/j.tiv.2014.02.015
[PubMed - indexed for MEDLINE]
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