Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer.
Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer.
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DOI：
10.1021/acschembio.5b00053
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发表时间：
2015-07-17
影响因子：
4
通讯作者：
Nomura DK
中科院分区：
文献类型：
--
作者：
Kohnz RA;Mulvihill MM;Chang JW;Hsu KL;Sorrentino A;Cravatt BF;Bandyopadhyay S;Goga A;Nomura DK
靶向失调的代谢途径是根除癌症的有希望的治疗策略。了解改变的癌基因调节代谢酶靶点的频率将有助于确定癌症的广谱和靶向代谢疗法。在这里，我们使用活性为基础的蛋白质谱，以确定丝氨酸水解酶的活动，一致上调各种人类癌基因。通过这种分析，我们发现了几种癌症相关丝氨酸水解酶的致癌调控机制，并发现血小板活化因子乙酰水解酶1B2和1B3（PAFAH1B2和PAFAH1B3）的活性一直上调几种癌基因，以及以前发现的癌症相关水解酶脂肪酸合成酶和单酰基甘油脂肪酶。虽然我们以前表明PAFAH1B2和1B3在乳腺癌中很重要，但我们最近的分析研究表明，这些酶可能在许多类型的癌症中广泛失调。在这里，我们发现两种酶的药理学阻断损害了多种不同类型癌细胞的癌症致病性，包括乳腺癌、卵巢癌、黑色素瘤和前列腺癌。我们还表明，PAFAH1B2和1B3的药理学阻断引起脂质代谢的独特变化，包括肿瘤抑制脂质水平的升高。我们的研究结果揭示了致癌调控机制的几个癌症相关的丝氨酸水解酶使用活性为基础的蛋白质分析，我们表明，PAFAH1B2和1B3是重要的，在维持癌症的致病性在广泛的癌症类型。
Targeting dysregulated metabolic pathways is a promising therapeutic strategy for eradicating cancer. Understanding how frequently altered oncogenes regulate metabolic enzyme targets would be useful in identifying both broad-spectrum and targeted metabolic therapies for cancer. Here, we used activity-based protein profiling to identify serine hydrolase activities that were consistently upregulated by various human oncogenes. Through this profiling effort, we found oncogenic regulatory mechanisms for several cancer-relevant serine hydrolases and discovered that platelet activating factor acetylhydrolase 1B2 and 1B3 (PAFAH1B2 and PAFAH1B3) activities were consistently upregulated by several oncogenes, alongside previously discovered cancer-relevant hydrolases fatty acid synthase and monoacylglycerol lipase. While we previously showed that PAFAH1B2 and 1B3 were important in breast cancer our most recent profiling studies have revealed that these enzymes may be dysregulated broadly across many types of cancers. Here, we find that pharmacological blockade of both enzymes impairs cancer pathogenicity across multiple different types of cancer cells, including breast, ovarian, melanoma, and prostate cancer. We also show that pharmacological blockade of PAFAH1B2 and 1B3 cause unique changes in lipid metabolism, including heightened levels of tumor-suppressing lipids. Our results reveal oncogenic regulatory mechanisms of several cancer-relevant serine hydrolases using activity-based protein profiling and we show that PAFAH1B2 and 1B3 are important in maintaining cancer pathogenicity across a wide spectrum of cancer types.