Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.

The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.

Nature communications. 2016 May 19*** epublish ***

Akash K Kaushik, Ali Shojaie, Katrin Panzitt, Rajni Sonavane, Harene Venghatakrishnan, Mohan Manikkam, Alexander Zaslavsky, Vasanta Putluri, Vihas T Vasu, Yiqing Zhang, Ayesha S Khan, Stacy Lloyd, Adam T Szafran, Subhamoy Dasgupta, David A Bader, Fabio Stossi, Hangwen Li, Susmita Samanta, Xuhong Cao, Efrosini Tsouko, Shixia Huang, Daniel E Frigo, Lawrence Chan, Dean P Edwards, Benny A Kaipparettu, Nicholas Mitsiades, Nancy L Weigel, Michael Mancini, Sean E McGuire, Rohit Mehra, Michael M Ittmann, Arul M Chinnaiyan, Nagireddy Putluri, Ganesh S Palapattu, George Michailidis, Arun Sreekumar

Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Zoology, Maharaja Sayajirao University of Baroda, Vadodara 390002, India., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA., Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Statistics, University of Michigan, Ann Arbor, Michigan 48109, USA., Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.