Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kaushik, AK; Shojaie, A; Panzitt, K; Sonavane, R; Venghatakrishnan, H; Manikkam, M; Zaslavsky, A; Putluri, V; Vasu, VT; Zhang, Y; Khan, AS; Lloyd, S; Szafran, AT; Dasgupta, S; Bader, DA; Stossi, F; Li, H; Samanta, S; Cao, X; Tsouko, E; Huang, S; Frigo, DE; Chan, L; Edwards, DP; Kaipparettu, BA; Mitsiades, N; Weigel, NL; Mancini, M; McGuire, SE; Mehra, R; Ittmann, MM; Chinnaiyan, AM; Putluri, N; Palapattu, GS; Michailidis, G; Sreekumar, A.
Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.
Nat Commun. 2016; 7(7):11612-11612
Doi: 10.1038/ncomms11612
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
- Cell Line -
- Hexosamines - biosynthesis
- Humans -
- Male -
- Mice -
- Mice, SCID -
- Phosphatidylinositol 3-Kinases - metabolism
- Prostatic Neoplasms, Castration-Resistant - drug therapy
- Prostatic Neoplasms, Castration-Resistant - metabolism
- Proto-Oncogene Proteins c-akt - metabolism