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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.

Author information

1
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
2
Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX 79106, USA.
3
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Cancer Genetics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
5
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
6
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA. Electronic address: yideng@hi.umn.edu.

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.

PMID:
25176644
PMCID:
PMC4360961
DOI:
10.1016/j.celrep.2014.07.053
[Indexed for MEDLINE]
Free PMC Article
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