MEK Inhibitor Suppresses Expression of the miR-17-92 Cluster with G1-Phase Arrest in HT-29 Human Colon Cancer Cells and MIA PaCa-2 Pancreatic Cancer Cells

Anticancer Res. 2016 Sep;36(9):4537-43. doi: 10.21873/anticanres.11001.

Abstract

Background: MicroRNAs (miRNAs) are small non-coding RNAs, and the deregulated expression of miRNAs is associated with tumor development. Among these, the miR-17-92 cluster, including six mature miRNAs, is known as an oncogenic miRNA cluster because expression of the miR-17-92 cluster is frequently elevated in a variety of malignant tumors.

Materials and methods: We investigated whether a mitogen-activated protein kinase kinase (MEK) inhibitor, PD0325901, suppresses expression of the miR-17-92 cluster in HT-29 human colon cancer cells and MIA PaCa-2 pancreatic cancer cells.

Results: PD0325901 inhibited cell growth with G1-phase arrest and suppressed expression of the miR-17-92 cluster. Furthermore, phosphatase and tensin homolog (PTEN), which is a target molecule of the miR-17-92 cluster, was up-regulated by PD0325901. The exogenous expression of miR-17 slightly, but significantly reduced G1-phase arrest by PD0325901.

Conclusion: These results raise the possibility that a MEK inhibitor causes G1-phase arrest, at least partially, through suppression of the miR-17-92 cluster.

Keywords: G1-phase arrest; MEK inhibitor; PTEN; miR-17-92 cluster; microRNA.

MeSH terms

  • Benzamides / chemistry
  • Cell Cycle
  • Cell Cycle Checkpoints*
  • Cell Line, Tumor / drug effects
  • Cell Proliferation
  • Colonic Neoplasms / enzymology*
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / chemistry
  • Down-Regulation
  • Enzyme Inhibitors / chemistry
  • G1 Phase
  • Gene Expression Regulation, Neoplastic*
  • HT29 Cells / drug effects
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • MicroRNAs / genetics*
  • Multigene Family
  • Mutation
  • PTEN Phosphohydrolase / metabolism

Substances

  • Benzamides
  • Enzyme Inhibitors
  • MIRN17-92 microRNA, human
  • MicroRNAs
  • PD 0325901
  • Diphenylamine
  • MAP Kinase Kinase Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human