title: Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.
abstract: Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Krushna C
authors.initials: KC
authors.lastname: Patra
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Prashanth T
authors.initials: PT
authors.lastname: Bhaskar
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Miller
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Wheaton
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Chandel
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Allen
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Jha
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Gromoslaw A
authors.initials: GA
authors.lastname: Smolen
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Clasquin
authors.affiliation: Veterans Affairs Medical Center, White River Junction, VT 05009, USA.|Geisel School of Medicine at Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Brooks
authors.initials: B
authors.lastname: Robey
authors.affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.|Research & Development Section, Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006019:Glycolysis; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014183:Transplantation, Heterologous
chemical_list: D006593:Hexokinase
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