Arginine methyltransferase inhibitor 1 inhibits gastric cancer by downregulating eIF4E and targeting PRMT5

Toxicol Appl Pharmacol. 2017 Dec 1:336:1-7. doi: 10.1016/j.taap.2017.10.002. Epub 2017 Oct 4.

Abstract

Arginine methylation is carried out by protein arginine methyltransferase (PRMTs) family. Arginine methyltransferase inhibitor 1 (AMI-1) is mainly used to inhibit type I PRMT activity in vitro. However, the effects of AMI-1 on type II PRMT5 activity and gastric cancer (GC) remain unclear. In this study, we provided the first evidence that AMI-1 significantly inhibited GC cell proliferation and migration while induced GC cell apoptosis, and reduced the expression of PRMT5, eukaryotic translation initiation factor 4E (eIF4E), symmetric dimethylation of histone 3 (H3R8me2s) and histone 4 (H4R3me2s). In addition, AMI-1 inhibited tumor growth, downregulated eIF4E, H4R3me2s and H3R8me2s expression in mice xenografts model of GC. Collectively, our results suggest that AMI-1 inhibits GC by downregulating eIF4E and targeting type II PRMT5.

Keywords: Arginine methyltransferase inhibitor 1 (AMI-1); Gastric cancer; Histonemethylation; Protein arginine methyltransferase 5 (PRMT5); eIF4E.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology*
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Female
  • Histones / metabolism
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / pathology
  • Time Factors
  • Tumor Burden / drug effects

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Eukaryotic Initiation Factor-4E
  • Histones
  • Repressor Proteins
  • eIF4E protein, mouse
  • PRMT1 protein, human
  • PRMT5 protein, human
  • Prmt1 protein, mouse
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases