Polyphyllin I suppresses the formation of vasculogenic mimicry via Twist1/VE-cadherin pathway

Cell Death Dis. 2018 Sep 5;9(9):906. doi: 10.1038/s41419-018-0902-5.

Abstract

Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells and is related to the metastasis and poor prognosis of many cancer types, including hepatocellular carcinoma (HCC). Thus far, no effective drugs have been developed to target VM. In this study, patients with liver cancer exhibited reduced VM in tumor tissues after treatment with Rhizoma Paridis. Polyphyllin I (PPI), which is the main component of Rhizoma Paridis, inhibited VM formation in HCC lines and transplanted hepatocellular carcinoma cells. Molecular mechanism analysis showed that PPI impaired VM formation by blocking the PI3k-Akt-Twist1-VE-cadherin pathway. PPI also displayed dual effects on Twist1 by inhibiting the transcriptional activation of the Twist1 promoter and interfering with the ability of Twist1 to bind to the promoter of VE-cadherin, resulting in VM blocking. This study is the first to report on the clinical application of the VM inhibitor. Results may contribute to the development of novel anti-VM drugs in clinical therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Cadherins / metabolism*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Diosgenin / analogs & derivatives*
  • Diosgenin / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / metabolism
  • Nuclear Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic / drug effects
  • Transcription, Genetic / drug effects
  • Twist-Related Protein 1 / metabolism*

Substances

  • Antigens, CD
  • Cadherins
  • Nuclear Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • cadherin 5
  • polyphyllin I
  • Phosphatidylinositol 3-Kinases
  • Diosgenin