Glycolytic inhibitor 2-Deoxy-d-Glucose activates migration and invasion in glioblastoma cells through modulation of the miR-7-5p/TFF3 signaling pathway

Biochem Biophys Res Commun. 2018 May 23;499(4):829-835. doi: 10.1016/j.bbrc.2018.04.001. Epub 2018 Apr 12.

Abstract

Glioblastomas (GBMs) are characterized by the metabolic shift towards aerobic glycolysis, rapid proliferation and acquisition of the migratory and invasive phenotype aiding tumor angiogenesis. The glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) used for targeting glycolysis in GBMs is ineffective in inhibiting migration and invasion. In the present study we report that 2-DG treatment downregulates the tumor suppressive miR-7-5p in GBM cell lines in vitro. Overexpression of miR-7-5p significantly reduced migration and invasion in GBM cell lines. The 2-DG induced suppression of miR-7-5p in turn activated the PI3K/Akt signaling activator Trefoil Factor 3 (TFF3) in GBM cell lines. TFF3 was found to be upregulated in cell lines and clinical samples and its genomic inhibition significantly decreased migration and invasion in GBM cell lines either alone or in combination with 2-DG. Collectively, our results provide the molecular basis for the limited efficacy of 2-DG monotherapy and underscores the significance of the miR-7-5p/TFF3 signaling pathway in the regulation of migration and invasion in 2-DG treated GBM cell lines.

Keywords: 2-Deoxy-d-glucose; Glioblastoma; Invasion; Migration; TFF3; miRNA -7-5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Deoxyglucose / pharmacology*
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / genetics*
  • Glioblastoma / pathology*
  • Glycolysis / drug effects*
  • Glycolysis / genetics
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Signal Transduction* / drug effects
  • Trefoil Factor-3 / metabolism*

Substances

  • 3' Untranslated Regions
  • MIRN7 microRNA, human
  • MicroRNAs
  • TFF3 protein, human
  • Trefoil Factor-3
  • Deoxyglucose