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

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 () and Arun Sreekumar ()
Additional contact information
Akash K. Kaushik: Baylor College of Medicine
Ali Shojaie: University of Washington
Katrin Panzitt: Baylor College of Medicine
Rajni Sonavane: Baylor College of Medicine
Harene Venghatakrishnan: Comprehensive Cancer Center, University of Michigan
Mohan Manikkam: Baylor College of Medicine
Alexander Zaslavsky: Comprehensive Cancer Center, University of Michigan
Vasanta Putluri: Baylor College of Medicine
Vihas T. Vasu: Maharaja Sayajirao University of Baroda
Yiqing Zhang: Baylor College of Medicine
Ayesha S. Khan: Center for Nuclear Receptors and Cell Signaling, University of Houston
Stacy Lloyd: Baylor College of Medicine
Adam T. Szafran: Baylor College of Medicine
Subhamoy Dasgupta: Baylor College of Medicine
David A. Bader: Baylor College of Medicine
Fabio Stossi: Baylor College of Medicine
Hangwen Li: Comprehensive Cancer Center, University of Michigan
Susmita Samanta: Baylor College of Medicine
Xuhong Cao: Comprehensive Cancer Center, University of Michigan
Efrosini Tsouko: Center for Nuclear Receptors and Cell Signaling, University of Houston
Shixia Huang: Baylor College of Medicine
Daniel E. Frigo: Center for Nuclear Receptors and Cell Signaling, University of Houston
Lawrence Chan: Baylor College of Medicine
Dean P. Edwards: Baylor College of Medicine
Benny A. Kaipparettu: Baylor College of Medicine
Nicholas Mitsiades: Baylor College of Medicine
Nancy L. Weigel: Baylor College of Medicine
Michael Mancini: Baylor College of Medicine
Sean E. McGuire: Baylor College of Medicine
Rohit Mehra: Comprehensive Cancer Center, University of Michigan
Michael M. Ittmann: Baylor College of Medicine
Arul M. Chinnaiyan: Comprehensive Cancer Center, University of Michigan
Nagireddy Putluri: Baylor College of Medicine
Ganesh S. Palapattu: Comprehensive Cancer Center, University of Michigan
George Michailidis: University of Michigan
Arun Sreekumar: Baylor College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11612

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