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 TsoukoShixia Huang, Daniel 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

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Article number11612
JournalNature Communications
Volume7
DOIs
StatePublished - May 19 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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