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

Research output: Contribution to journalArticlepeer-review

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

Bibliographical note

Funding Information:
This work is supported, in part, by grants from the US National Cancer Institute (K01 CA124461, Y.D.; R01 CA160333, Y.D; R21 CA155522, Y.D. and J.L; R01 CA172169, J.L. and Y.D; R01 CA130908 and R01 CA134514, H.H; R01 CA164346, M.J.Y.), the University of Minnesota Grant-in Aid (Y.D.), and start-up funds from the Hormel Foundation (Y.D.).

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