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

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.

Glycosylation is a global target for androgen control in prostate cancer cells

“…The transcript levels of HBP genes are downregulated in CRPC tissue compared with localised hormonesensitive tumours, and loss of GNPNAT1 in CRPC cells increases tumour growth and aggressiveness in mouse models in cells containing either AR-full length of AR-V7 (Kaushik et al 2016). In castrate-resistant disease, the HBP can be targeted therapeutically by treatment with UDP-GlcNAc, which remarkably increases the efficacy of the anti-androgen enzalutamide also (Kaushik et al 2016). Increased glycolysis is one of the main metabolic adaptations found in CRPC (Biernacka et al 2013).…”

“…Although HBP is regulated by the AR and is upregulated in localised hormone-sensitive prostate cancer where it has a positive influence on disease progression, in the castrate-resistant state, downregulation of HBP appears to enhance tumour growth and is a key biochemical mediator of CRPC progression (Kaushik et al 2016). The transcript levels of HBP genes are downregulated in CRPC tissue compared with localised hormonesensitive tumours, and loss of GNPNAT1 in CRPC cells increases tumour growth and aggressiveness in mouse models in cells containing either AR-full length of AR-V7 (Kaushik et al 2016).…”

“…Established role in synthesising O-GlcNAc which is elevated in numerous cancer types and has itself been described as a hallmark of cancer (Fardini et al 2013, Ma & Vosseller 2014 GNPNAT1 is decreased in CRPC (Kaushik et al 2016). Inhibition of HBP suggested as a potential therapy in CRPC (Kaushik et al 2016) Chondroitin sulfate synthesis CSGALNACT1 Initiation of chondroitin sulfate (CS) synthesis CS is a key molecule in cancer progression (Theocharis et al 2006).…”

“…HBP potential target in CRPC (Kaushik et al 2016) Established role in synthesising O-GlcNAc which is elevated in numerous cancer types and has itself been described as a hallmark of cancer (Fardini et al 2013, Ma & Vosseller 2014 Androgen regulated and linked to prostate cancer cell viability (Lee et al 2010. HBP is a potential target in CRPC (Kaushik et al 2016) GNPNAT1 Second enzyme in the hexosamine biosynthetic pathway (HBP)…”

“…Inhibition of HBP suggested as a potential therapy in CRPC (Kaushik et al 2016) Chondroitin sulfate synthesis CSGALNACT1 Initiation of chondroitin sulfate (CS) synthesis CS is a key molecule in cancer progression (Theocharis et al 2006). The large CS proteoglycan Versican is linked to poor prognosis in many different cancer types (Ricciardelli et al 2009b).…”