Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth

Lei Wang, Hua Xiong, Fengxia Wu, Yingjie Zhang, Ji Wang, Liyan Zhao, Xiaolan Guo, Li Ju Chang, Yong Zhang, M. James You, Shahriar Koochekpour, Mohammad Saleem, Haojie Huang, Junxuan Lu, Yibin Deng

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Abstract

Accumulating evidence suggests that codeletion ofthe tumor suppressor genes Pten and p53 plays a crucial role in the development of castration-resistant prostate cancer invivo. 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.

Original languageEnglish (US)
Pages (from-to)1461-1474
Number of pages14
JournalCell Reports
Volume8
Issue number5
DOIs
StatePublished - Jan 1 2014

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wang, L., Xiong, H., Wu, F., Zhang, Y., Wang, J., Zhao, L., Guo, X., Chang, L. J., Zhang, Y., You, M. J., Koochekpour, S., Saleem, M., Huang, H., Lu, J., & Deng, Y. (2014). Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth. Cell Reports, 8(5), 1461-1474. https://doi.org/10.1016/j.celrep.2014.07.053