title: Regulatory role of hexosamine biosynthetic pathway on hepatic cancer stem cell marker CD133 under low glucose conditions.
abstract: Cancer was hypothesized to be driven by cancer stem cells (CSCs), but the metabolic determinants of CSC-like phenotype still remain elusive. Here, we present that hexosamine biosynthetic pathway (HBP) at least in part rescues cancer cell fate with inactivation of glycolysis. Firstly, metabolomic analysis profiled cellular metabolome in CSCs of hepatocellular carcinoma using CD133 cell-surface marker. The metabolic signatures of CD133-positive subpopulation compared to CD133-negative cells highlighted HBP as one of the distinct metabolic pathways, prompting us to uncover the role of HBP in maintenance of CSC-like phenotype. To address this, CSC-like phenotypes and cell survival were investigated in cancer cells under low glucose conditions. As a result, HBP inhibitor azaserine reduced CD133-positive subpopulation and CD133 expression under high glucose condition. Furthermore, treatment of N-Acetylglucosamine in part restores CD133-positive subpopulation when either 2.5 mM glucose in culture media or glycolytic inhibitor 2-deoxy-D-glucose in HCC cell lines was applied, enhancing CD133 expression as well as promoting cancer cell survival. Together, HBP might be a key metabolic determinant in the functions of hepatic CSC marker CD133.
authors.affiliation: State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR.
authors.forename: Shu-Hai
authors.initials: SH
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ming
authors.affiliation: State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Shenzhen University Cancer Center, Shenzhen, 518060, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.affiliation: Helmholtz-Zentrum Muenchen-German Research Center for Environmental Health, Research Unit of analytical Biogeochemistry, Ingolstaedter Landstrasse 1, D-85764 Oberschleißheim, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schmitt-Kopplin
authors.affiliation: Helmholtz-Zentrum Muenchen-German Research Center for Environmental Health, Research Unit of analytical Biogeochemistry, Ingolstaedter Landstrasse 1, D-85764 Oberschleißheim, Germany.
authors.forename: Basem
authors.initials: B
authors.lastname: Kanawati
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D001377:Azaserine / Q000494:pharmacology; D015415:Biomarkers; D053898:Biosynthetic Pathways / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype
chemical_list: D000071916:AC133 Antigen; D015415:Biomarkers; D006595:Hexosamines; D001377:Azaserine; D005947:Glucose