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

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

146 Scopus citations

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 - 2014

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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.",

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

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doi = "10.1016/j.celrep.2014.07.053",

language = "English (US)",

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T1 - Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth

AU - Wang, Lei

AU - Xiong, Hua

AU - Wu, Fengxia

AU - Zhang, Yingjie

AU - Wang, Ji

AU - Zhao, Liyan

AU - Guo, Xiaolan

AU - Chang, Li Ju

AU - Zhang, Yong

AU - You, M. James

AU - Koochekpour, Shahriar

AU - Saleem, Mohammad

AU - Huang, Haojie

AU - Lu, Junxuan

AU - Deng, Yibin

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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

Abstract

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