Open Access Highly Accessed Research article

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

Jun Terashima1*, Chie Tachikawa12, Kenzo Kudo2, Wataru Habano1 and Shogo Ozawa1

Author Affiliations

1 Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun 028-3694, Iwate, Japan

2 Department of Pharmacy, Iwate medical University Hospital, 19-1 Uchimaru, Morioka 020-8505, Iwate, Japan

For all author emails, please log on.

BMC Molecular Biology 2013, 14:27  doi:10.1186/1471-2199-14-27

Published: 12 December 2013

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.

Keywords:
Aryl hydrocarbon receptor (AhR); Vascular endothelial growth factor (VEGF); Angiogenesis; Activating transcription factor 4 (ATF4); Human hepatocellular liver carcinoma cell