Abstract
BackgroundAryl 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).ResultsRecently, 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.ConclusionsThe 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.
Highlights
Aryl hydrocarbon receptor (AhR) regulates drug-metabolizing enzyme expression and regulates cancer malignancy
When the medium was exchanged from high glucose medium (4.5 g/L D-glucose) to no glucose medium (0 g/L), Vascular endothelial growth factor (VEGF) mRNA expression was increased in HepG2 cells at 12 and 24 h after the medium exchange (Figure 1A)
VEGF is a potent angiogenic factor that plays a central role in angiogenesis [11], and angiogenesis is a significant step in the pre-malignancy and malignancy of cancer [21]
Summary
Aryl hydrocarbon receptor (AhR) regulates drug-metabolizing enzyme expression and regulates cancer malignancy. 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). One of the nutrient deprivations of MCF-7/ADR cells, induces the expression of cellular homologs of oncogenes and angiogenic factors [14,15]. These results support the hypothesis that glycolytic metabolism is associated with cancer malignancy [16]. We report a novel pathway that induces VEGF expression in HepG2 cells in response to glucose deprivation. The response to glucose deprivation that is mediated by AhR induces VEGF expression through activating transcription factor 4 (ATF4) expression in HepG2 cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
