Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.
Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer.
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DOI：
10.1038/ncomms11612
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发表时间：
2016-05-19
影响因子：
16.6
通讯作者：
Sreekumar A
中科院分区：
文献类型：
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作者：
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
驱动去势抵抗性前列腺癌（CRPC）的精确分子改变尚不清楚。使用一种新的基于网络的综合方法，我们发现己糖胺生物合成途径（HBP）的明显改变对CRPC至关重要。与局限性前列腺癌（PCa）相比，CRPC中HBP酶葡萄糖胺-磷酸n -乙酰转移酶1 （GNPNAT1）的表达明显降低。在体外和体内，基因功能缺失的GNPNAT1在crpc样细胞中增加增殖和侵袭性。这是由表达全长雄激素受体（AR）的细胞中PI3K-AKT通路的激活或含有AR- v7变体的细胞中特定蛋白1 （SP1）调节的碳水化合物反应元件结合蛋白（ChREBP）的表达介导的。引人注目的是，在体外和动物实验中，将HBP代谢物udp - n-乙酰氨基葡萄糖（UDP-GlcNAc）添加到crpc样细胞中可显著降低细胞增殖，同时在体外与enzalutamide联合使用时也显示出附加效果。这些观察结果证明了靶向HBP治疗CRPC的治疗价值。前列腺癌中驱动抗雄激素抵抗的分子改变尚不清楚。在这里，作者使用基于网络的方法表明，抑制己糖胺生物合成途径对于产生耐药性是必要的，并且增加该途径的活性可以增强抗雄激素反应。
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. The molecular alterations driving anti-androgen resistance in prostate cancer are unclear. Here, the authors show, using a network-based approach, that inhibition of the hexosamine biosynthetic pathway is necessary to develop resistance and that increasing the activity of the pathway enhances the anti-androgen response.