Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
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DOI：
10.1038/nature07762
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发表时间：
2009-02-12
期刊：
影响因子：
64.8
通讯作者：
Chinnaiyan, Arul M.
中科院分区：
文献类型：
--
作者：
Sreekumar, Arun;Poisson, Laila M.;Rajendiran, Thekkelnaycke M.;Khan, Amjad P.;Cao, Qi;Yu, Jindan;Laxman, Bharathi;Mehra, Rohit;Lonigro, Robert J.;Li, Yong;Nyati, Mukesh K.;Ahsan, Aarif;Kalyana-Sundaram, Shanker;Han, Bo;Cao, Xuhong;Byun, Jaeman;Omenn, Gilbert S.;Ghosh, Debashis;Pennathur, Subramaniam;Alexander, Danny C.;Berger, Alvin;Shuster, Jeffrey R.;Wei, John T.;Varambally, Sooryanarayana;Beecher, Christopher;Chinnaiyan, Arul M.
多种复杂的分子事件是癌症发生和发展的特征。解读区分器官局限性疾病和转移性疾病的分子网络，可能会导致识别出癌症侵袭和疾病侵袭性的关键生物标志物。尽管基因和蛋白质表达已在人类肿瘤中得到广泛分析，但对于肿瘤进展所特有的整体代谢组变化知之甚少。我们利用基于高通量液相和气相色谱的质谱联用技术，对262例前列腺癌临床样本（42个组织样本以及各110个尿液和血浆样本）中的1126种以上代谢物进行了分析。这些无偏的代谢组图谱能够区分良性前列腺、临床局限性前列腺癌和转移性疾病。肌氨酸，一种氨基酸甘氨酸的N - 甲基衍生物，被确定为一种差异代谢物，在前列腺癌进展为转移的过程中高度升高，并且可以在尿液中无创检测到。与良性前列腺上皮细胞相比，侵袭性前列腺癌细胞系中的肌氨酸水平也升高。甘氨酸 - N - 甲基转移酶（GNMT）是一种将甘氨酸转化为肌氨酸的酶，抑制该酶可减弱前列腺癌的侵袭性。添加外源性肌氨酸或抑制导致肌氨酸降解的酶（肌氨酸脱氢酶，SARDH），会使良性前列腺上皮细胞产生侵袭表型。雄激素受体和ERG基因融合产物协同调节肌氨酸途径的组成部分。综上所述，我们分析了前列腺癌进展过程中的代谢组变化，揭示了肌氨酸是癌细胞侵袭和侵袭性的一种潜在重要代谢中间产物。
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumors, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high throughput liquid and gas chromatography-based mass spectrometry, we profiled more than 1126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer, and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly elevated during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also elevated in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase (GNMT), the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase (SARDH), induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Taken together, we profiled the metabolomic alterations of prostate cancer progression revealing sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
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DOI：
10.1111/1467-9868.00346
发表时间：
2002-01-01
影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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