Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells.
Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells.
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DOI：
10.18632/oncotarget.5585
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发表时间：
2015-10-13
期刊：
影响因子：
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通讯作者：
Weigel NL
中科院分区：
文献类型：
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作者：
Shafi AA;Putluri V;Arnold JM;Tsouko E;Maity S;Roberts JM;Coarfa C;Frigo DE;Putluri N;Sreekumar A;Weigel NL
转移性前列腺癌(PCa)主要是一种雄激素依赖型疾病，采用雄激素剥夺疗法(ADT)治疗。肿瘤通常产生抵抗(去势抵抗的PCa[CRPC])，但仍依赖雄激素受体(AR)。许多AR依赖的抗性机制已被确定，包括表达具有结构性活性的AR剪接变异体，缺少激素结合域。最近的临床研究表明，最具特征性的AR变异体AR-V7的表达与ADT耐药和不良预后相关。AR-V7是仅仅是AR的结构性活性替代品，还是具有引起独特下游变化的新的基因靶点，目前还没有解决的问题。一些研究表明，AR的激活改变了细胞的新陈代谢。以AR-V7可诱导表达的LNCaP细胞为模型系统，我们发现AR-V7刺激生长、迁移和糖酵解，以与AR相似的细胞外酸化率(ECAR)来衡量。然而，使用代谢组学和代谢通量分析的进一步分析显示了几个差异。AR增加了柠檬酸水平，AR-V7降低了柠檬酸，反映了CRPC患者观察到的代谢变化。通量分析表明，柠檬酸盐含量低是利用率提高的结果，而不是合成柠檬酸盐失败的结果。此外，通量分析表明，与AR相比，AR-V7表现出更多对谷氨酰胺分解和还原羧化的依赖，以产生一些TCA(三羧酸循环)代谢物。这些发现表明，这些独特的行动代表了潜在的治疗靶点。
Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets.