Elevated glucose levels impair the WNT/β-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer. Issue 159 (May 2016)

• Record Type: Journal Article
• Authors: Zhou, Fuxing; Huo, Junwei; Liu, Yu; Liu, Haixia; Liu, Gaowei; Chen, Ying; Chen, Biliang
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 159(2016)
• Page Start: 19
• Page End: 25
• Publication Date: 2016-05
• Subjects: Elevated glucose levels -- WNT/β-catenin -- O-GlcNAc -- Endometrial cancer; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2016.02.015
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: AN3CA and HEC-1-B cells showed high β-catenin expression under elevated glucose levels. Both cell lines also exhibited an increase in O -GlcNAcylation levels. β-catenin expression increases via activation of HBP in both cell lines. Glucose-induced β-catenin elevation triggers the transcription of target genes. Abstract: Endometrial cancer (EC) is one of the most common gynecological malignancies in the world. Associations between fasting glucose levels (greater than 5.6 mmol/L) and the risk of cancer fatality have been reported. However, the underlying link between glucose metabolic disease and EC remains unclear. In the present study, we explored the influence of elevated glucose levels on the WNT/β-catenin pathway in EC. Previous studies have suggested that elevated concentrations of glucose can drive the hexosamine biosynthesis pathway (HBP) flux, thereby enhancing the O-GlcNAc modification of proteins. Here, we cultured EC cell lines, AN3CA and HEC-1-B, with various concentrations of glucose. Results showed that when treated with high levels of glucose, both lines showed increased expression of β-catenin and O-GlcNAcylation levels; however, these effects could be abolished by the HBP inhibitors, Azaserine and 6-Diazo-5-oxo-l- norleucine, and be restored by glucosamine. Moreover the AN3CA and HEC-1-B cells that were cultured with or without PUGNAc, an inhibitor of the O-GlcNAcase, showed that PUGNAc increased β-catenin levels. The results suggest that elevated glucose levels increase β-catenin expression via the activation of the HBP in EC cells. Subcellular fractionation experiments showed that AN3CA cells had a higher expression of intranuclear β-catenin in high glucose medium. Furthermore, TOP/FOP-Flash and RT-PCR results showed that glucose-induced increased expression of β-catenin triggered the transcription of target genes. In conclusion, elevated glucose levels, via HBP, increase the O-GlcNAcylation level, thereby inducing the over expression of β-catenin and subsequent transcription of the target genes in EC cells.