title: JC virus T-antigen regulates glucose metabolic pathways in brain tumor cells.
abstract: Recent studies have reported the detection of the human neurotropic virus, JCV, in a significant population of brain tumors, including medulloblastomas. Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin. Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as β-catenin and IRS-1, plays a role in the oncogenic function of JCV T-antigen. We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells and in glioblastoma xenografts that both endogenously express T-antigen. Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by 5'-activated AMP kinase (AMPK), an important sensor of the AMP/ATP ratio in cells. In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation. Furthermore, T-antigen prevents G1 arrest and sustains cells in the G2 phase during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on reactive oxygen species (ROS) production during glucose deprivation, and T-antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation. Additionally, we have found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamide and oxythiamine, and that T-antigen modulates expression of the glycolytic enzyme, hexokinase 2 (HK2), and the pentose phosphate enzyme, transaldolase-1 (TALDO1), indicating a potential link between T-antigen and metabolic regulation. These studies point to the possible involvement of JCV T-antigen in medulloblastoma proliferation and the metabolic phenotype and may enhance our understanding of the role of viral proteins in glycolytic tumor metabolism, thus providing useful targets for the treatment of virus-induced tumors.
authors.affiliation: Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Evan
authors.initials: E
authors.lastname: Noch
authors.forename: Ilker Kudret
authors.initials: IK
authors.lastname: Sariyer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D015120:6-Aminonicotinamide / Q000494:pharmacology; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000032:analysis / Q000378:metabolism*; D000963:Antimetabolites / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D015536:Down-Regulation; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000096:biosynthesis; D006801:Humans; D007577:JC Virus / Q000187:drug effects / Q000378:metabolism*; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D010119:Oxythiamine / Q000494:pharmacology; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014153:Transaldolase / Q000096:biosynthesis
chemical_list: D000957:Antigens, Viral, Tumor; D000963:Antimetabolites; D017382:Reactive Oxygen Species; D010119:Oxythiamine; D015120:6-Aminonicotinamide; D003847:Deoxyglucose; D014153:Transaldolase; D006593:Hexokinase; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose