1. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.
- Author
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Kaushik, Akash, Shojaie, Ali, Panzitt, Katrin, Sonavane, Rajni, Venghatakrishnan, Harene, Manikkam, Mohan, Zaslavsky, Alexander, Putluri, Vasanta, Vasu, Vihas, Zhang, Yiqing, Khan, Ayesha, Lloyd, Stacy, Szafran, Adam, Dasgupta, Subhamoy, Bader, David, Stossi, Fabio, Li, Hangwen, Samanta, Susmita, Cao, Xuhong, Tsouko, Efrosini, Huang, Shixia, Frigo, Daniel, Chan, Lawrence, Edwards, Dean, Kaipparettu, Benny, Mitsiades, Nicholas, Weigel, Nancy, Mancini, Michael, McGuire, Sean, Mehra, Rohit, Ittmann, Michael, Chinnaiyan, Arul, Putluri, Nagireddy, Palapattu, Ganesh, Michailidis, George, and Sreekumar, Arun
- Subjects
Animals ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Cell Line ,Hexosamines ,Humans ,Male ,Mice ,Mice ,SCID ,Phosphatidylinositol 3-Kinases ,Prostatic Neoplasms ,Castration-Resistant ,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 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.
- Published
- 2016