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
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, ‡Alkek Center for Molecular Discovery, §Molecular and Cellular Biology, and ∥Department of Surgery, Baylor College of Medicine , Houston, Texas 77030, United States.
J Proteome Res. 2014 Feb 7;13(2):1088-100. doi: 10.1021/pr401106h. Epub 2013 Dec 31.
Despite recent developments in treatment strategies, castration-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.
尽管治疗策略最近有所发展，但去势抵抗性前列腺癌（CRPC）仍是美国男性癌症相关死亡的第二大主要原因，其生物学基础尚不清楚。为此，我们使用靶向质谱和代谢表型分析相结合的方法，测量了转移性雄激素依赖性前列腺癌（AD）和CRPC细胞系中150种代谢物的水平，并检测了184种代谢物的利用速率。利用Oncomine概念图（OCM），代谢数据被用于推导在CRPC中富集的生化途径。然后，使用已发表的临床注释基因表达数据集，在计算机上检查这些富集途径与治疗失败（即前列腺特异性抗原（PSA）复发或生化复发）的关联。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一个高度互联的生化途径网络，该网络描述了UDP葡萄糖醛酸转移酶（UGT）的活性。在三个独立的基因表达数据集中，我们在一项使用限于该途径的基因的分析中观察到与治疗失败时间的关联。总之，我们的研究突出了在细胞系中采用代谢组学策略以获得潜在临床有用预测工具的价值。
