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

doi:10.1016/j.celrep.2014.07.053

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 language	English (US)
Pages (from-to)	1461-1474
Number of pages	14
Journal	Cell Reports
Volume	8
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2014.07.053
State	Published - Sep 1 2014

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© 2014 The Authors.

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

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.",

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

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