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Updated: Mar 21, 2026
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer
Akash K Kaushik1,2, Ali Shojaie3, Katrin Panzitt1
1Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
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.
Insights
Castration-resistant prostate cancer (CRPC) involves altered hexosamine biosynthetic pathways (HBP). Decreased GNPNAT1 enzyme activity drives CRPC aggressiveness, but HBP metabolite UDP-GlcNAc shows therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Castration-resistant prostate cancer (CRPC) molecular drivers remain unclear.
- Prostate cancer (PCa) progression involves complex cellular changes.
Purpose of the Study:
- Investigate molecular alterations in CRPC using a network-based approach.
- Identify critical pathways involved in CRPC development and progression.
Main Methods:
- Employed a novel network-based integrative approach.
- Analyzed expression of hexosamine biosynthetic pathway (HBP) enzymes, specifically glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1).
- Utilized in vitro and in vivo models of CRPC-like cells, including manipulation of GNPNAT1 and androgen receptor (AR) variants.
Main Results:
- Found significantly decreased GNPNAT1 expression in CRPC compared to localized prostate cancer (PCa).
- Demonstrated that GNPNAT1 loss-of-function increases CRPC cell proliferation and aggressiveness via PI3K-AKT or SP1/ChREBP pathways.
- Showed that UDP-N-acetylglucosamine (UDP-GlcNAc) addition reduces CRPC cell proliferation and enhances enzalutamide efficacy.
Conclusions:
- Hexosamine biosynthetic pathway (HBP) alterations are critical in CRPC.
- Targeting HBP, particularly with UDP-GlcNAc, represents a promising therapeutic strategy for CRPC.
- Understanding specific pathway activations based on AR status is key for CRPC treatment.
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