title: Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth.
abstract: Accumulating evidence suggests that codeletion of the tumor suppressor genes Pten and p53 plays a crucial role in the development of castration-resistant prostate cancer in vivo. However, the molecular mechanism underlying Pten-/p53-deficiency-driven prostate tumorigenesis remains incompletely understood. Building upon insights gained from our studies with Pten-/p53-deficient mouse embryonic fibroblasts (MEFs), we report here that hexokinase 2 (HK2) is selectively upregulated by the combined loss of Pten and p53 in prostate cancer cells. Mechanistically, Pten deletion increases HK2 mRNA translation through the activation of the AKT-mTORC1-4EBP1 axis, and p53 loss enhances HK2 mRNA stability through the inhibition of miR143 biogenesis. Genetic studies demonstrate that HK2-mediated aerobic glycolysis, known as the Warburg effect, is required for Pten-/p53-deficiency-driven tumor growth in xenograft mouse models of prostate cancer. Our findings suggest that HK2 might be a therapeutic target for prostate cancer patients carrying Pten and p53 mutations.
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Fengxia
authors.initials: F
authors.lastname: Wu
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Chang
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX 79106, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Cancer Genetics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Koochekpour
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Saleem
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX 79106, USA.
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA. Electronic address: yideng@hi.umn.edu.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Deng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D006019:Glycolysis; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D006593:Hexokinase; C000598049:hexokinase 2, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse