title: Elevated glucose levels impair the WNT/β-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer.
abstract: Endometrial cancer (EC) is one of the most common gynecological malignancies in the world. Associations between fasting glucose levels (greater than 5.6mmol/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.
authors.affiliation: Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Gynecology and Obstetrics, The First Hospital of Yulin, Yulin, Shaanxi 718000, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Huo
authors.affiliation: Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Gaowei
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Natural Medicine, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: chenbiliang1962@sina.com.
authors.forename: Biliang
authors.initials: B
authors.lastname: Chen
mesh_terms: D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000502:physiology*; D006031:Glycosylation; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D011499:Protein Processing, Post-Translational; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D006595:Hexosamines; D051176:beta Catenin; D005947:Glucose
keywords: Elevated glucose levels; Endometrial cancer; O-GlcNAc; WNT/β-catenin