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

• DOI: 10.1038/ncomms11612
• Publication Date: 2016-05-20T20:37:08Z
• Authors: Akash K. Kaushik; Ali Shojaie; Katrin Panzitt; Rajni Sonavane; Harene Venghatakr...; 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
• Keywords: Male; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Science; Q; Prostatic Neoplasms; Hexosamines; Mice, SCID; SCID; Castration-Resistant; Article; Cell Line; 3. Good health; Mice; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms, Castration-Resistant; Animals; Humans; Proto-Oncogene Proteins c-akt

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 in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 ( GNPNAT1 ) is found significantly decreased CRPC compared with localized (PCa). Genetic loss-of-function CRPC-like cells increases proliferation and aggressiveness, vitro vivo . This mediated by either activation PI3K-AKT expressing full-length androgen receptor (AR) or specific protein (SP1)-regulated expression carbohydrate response element-binding (ChREBP) containing AR-V7 variant. Strikingly, addition metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) decreases cell proliferation, both in-vitro animal studies, while also demonstrates additive efficacy when combined enzalutamide These observations demonstrate therapeutic value targeting