An aryl hydrocarbon receptor induces VEGF expression through ATF4 under glucose deprivation in HepG2

BMC Mol Biol. 2013 Dec 12;14:27. doi: 10.1186/1471-2199-14-27.

Abstract

Background: Aryl hydrocarbon receptor (AhR) not only regulates drug-metabolizing enzyme expression but also regulates cancer malignancy. The steps to the development of malignancy include angiogenesis that is induced by tumor microenvironments, hypoxia, and nutrient deprivation. Vascular endothelial growth factor (VEGF) plays a central role in the angiogenesis of cancer cells, and it is induced by activating transcription factor 4 (ATF4).

Results: Recently, we identified that glucose deprivation induces AhR translocation into the nucleus and increases CYP1A1 and 1A2 expression in HepG2 cells. Here, we report that the AhR pathway induces VEGF expression in human hepatoblastoma HepG2 cells under glucose deprivation, which involves ATF4. ATF4 knockdown suppressed VEGF expression under glucose deprivation. Moreover, AhR knockdown suppressed VEGF and ATF4 expression under glucose deprivation at genetic and protein levels.

Conclusions: The AhR-VEGF pathway through ATF4 is a novel pathway in glucose-deprived liver cancer cells that is related to the microenvironment within a cancer tissue affecting liver cancer malignancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Cell Hypoxia
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Glucose / metabolism*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / physiology
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • ATF4 protein, human
  • Receptors, Aryl Hydrocarbon
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Activating Transcription Factor 4
  • Glucose