Metabolomic profiling identifies biochemical pathways associated with castration-resistant prostate cancer.
Metabolomic profiling identifies biochemical pathways associated with castration-resistant prostate cancer.
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DOI：
10.1021/pr401106h
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发表时间：
2014-02-07
影响因子：
4.4
通讯作者：
Sreekumar, Arun
中科院分区：
文献类型：
--
作者：
Kaushik, Akash K.;Vareed, Shaiju K.;Basu, Sumanta;Putluri, Vasanta;Putluri, Nagireddy;Panzitt, Katrin;Brennan, Christine A.;Chinnaiyan, Arul M.;Vergara, Ismael A.;Erho, Nicholas;Weigel, Nancy L.;Mitsiades, Nicholas;Shojaie, Ali;Palapattu, Ganesh;Michailidis, George;Sreekumar, Arun
关键词：
尽管最近在治疗策略方面取得了进展，但去势抵抗性前列腺癌（CRPC）仍然是美国男性癌症相关死亡率的第二大原因，其生物学基础尚不清楚。为此，我们测量了150种代谢物的水平，并使用靶向质谱和代谢表型分析的组合检查了184种代谢物在转移性雄激素依赖性前列腺癌（AD）和CRPC细胞系中的利用率。使用Oncomine概念图（OCM），使用代谢数据推导CRPC富集的生化途径。然后通过计算机模拟检查富集的途径与治疗失败的相关性（即，前列腺特异性抗原（PSA）复发或生化复发）。我们的结果表明，与AD细胞系相比，CRPC中共有19种代谢物发生了改变。这些改变的代谢物映射到描述UDP葡萄糖醛酸基转移酶（UGT）活性的高度互连的生化途径网络。我们在一项分析中观察到了与治疗失败时间的相关性，该分析采用了三个独立基因表达数据集中限制于该途径的基因。总之，我们的研究强调了在细胞系中采用代谢组学策略以获得潜在的临床有用的预测工具的价值。
Despite recent developments in treatment strategies, castrate resistant prostate cancer (CRPC) is still the second leading cause of cancer associated mortality among American men, the biological underpinnings of which are not well understood. To this end, we measured levels of 150 metabolites and examined the rate of utilization of 184 metabolites in metastatic androgen dependent prostate cancer (AD) and CRPC cell lines using a combination of targeted mass spectrometry and metabolic phenotyping. Metabolic data were used to derive biochemical pathways that were enriched in CRPC, using Oncomine Concept Maps (OCM). The enriched pathways were then examined in-silico for their association with treatment failure (i.e., prostate specific antigen (PSA) recurrence or biochemical recurrence) using published clinically annotated gene expression data sets. Our results indicate that a total of 19 metabolites were altered in CRPC compared to AD cell lines. These altered metabolites mapped to a highly interconnected network of biochemical pathways that describe UDP glucuronosyltransferase (UGT) activity. We observed an association with time to treatment failure in an analysis employing genes restricted to this pathway in three independent gene expression data sets. In summary, our studies highlight the value of employing metabolomic strategies in cell lines to derive potentially clinically useful predictive tools.
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