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Cell Rep. 2014 Sep 11;8(5):1461-74. doi: 10.1016/j.celrep.2014.07.053. Epub 2014 Aug 28.

Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth.

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Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX 79106, USA.
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Department of Cancer Genetics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA. Electronic address:


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.

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