Umbelliprenin isolated from Ferula sinkiangensis inhibits tumor growth and migration through the disturbance of Wnt signaling pathway in gastric cancer

PLoS One. 2019 Jul 1;14(7):e0207169. doi: 10.1371/journal.pone.0207169. eCollection 2019.

Abstract

The traditional herb medicine Ferula sinkiangensis K. M. Shen (F. sinkiangensis) has been used to treat stomach disorders in Xinjiang District for centuries. Umbelliprenin is the effective component isolated from F. sinkiangensis which is particularly found in plants of the family Ferula. We previously reported the promising effects of Umbelliprenin against gastric cancer cells, but its anti-migration effect remained unknown. Here we investigated the anti-migration effect and mechanism of Umbelliprenin in human gastric cancer cells. In SRB assay, Umbelliprenin showed cytotoxic activities in the gastric cancer cell lines AGS and BGC-823 in a dose-and-time-dependent manner, while it showed lower cytotoxic activity in the normal gastric epithelium cell line GES-1. During transwell, scratch and colony assays, the migration of tumor cells was inhibited by Umbelliprenin treatment. In gelatin zymography assay, Umbelliprenin could inhibit the expression of MMP2 and MMP9 in tumor cells The expression levels of the Wnt-associated signaling pathway proteins were analyzed with western blots, and the results showed that Umbelliprenin decreased the expression levels of proteins of the Wnt signalling pathway, such as Wnt-2, β-catenin, GSK-3β, p-GSK-3β, Survivin and c-myc. The translocation of β-catenin to the nucleus was also inhibited by Umbelliprenin treatment. In TCF reporter assay, the transcriptional activity of T-cell factor/lymphoid enhancer factor (TCF/LEF) was decreased after Umbelliprenin treatment. The in vivo results suggested that Umbelliprenin induced little to no harm in the lung, heart and kidney. Overall, these data provided evidence that Umbelliprenin may inhibit the growth, invasion and migration of gastric cancer cells by disturbing the Wnt signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Ferula / chemistry*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Proteins / metabolism*
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • Umbelliferones* / chemistry
  • Umbelliferones* / pharmacology
  • Wnt Signaling Pathway / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Neoplasm Proteins
  • Umbelliferones
  • umbelliprenin

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81460661 and No. 81460586), the Ministry of Science and Technology of the People's Republic of China, and the Major Scientific and Technological Special Project for ‘‘Significant New Drugs Formulation’’ (Grant No. 2012ZX09501001-004 and 2012ZX09301-002-001-026). This work was also supported by the Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences.