Kohnz Rebecca A, Mulvihill Melinda M, Chang Jae Won, Hsu Ku-Lung, Sorrentino Antonio, Cravatt Benjamin F, Bandyopadhyay Sourav, Goga Andrei, Nomura Daniel K
†Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, California 94720, United States.
‡Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR107, La Jolla, California 92037, United States.
ACS Chem Biol. 2015 Jul 17;10(7):1624-30. doi: 10.1021/acschembio.5b00053. Epub 2015 May 7.
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 causes 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.
针对失调的代谢途径是根除癌症的一种有前景的治疗策略。了解癌基因调控代谢酶靶点的频繁程度，对于确定癌症的广谱和靶向代谢疗法都将有所帮助。在此，我们利用基于活性的蛋白质谱分析来鉴定各种人类癌基因持续上调的丝氨酸水解酶活性。通过这项谱分析工作，我们发现了几种与癌症相关的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）的活性与之前发现的与癌症相关的水解酶脂肪酸合酶和单酰甘油脂肪酶一样，被几种癌基因持续上调。虽然我们之前表明PAFAH1B2和1B3在乳腺癌中很重要，但我们最近的谱分析研究表明，这些酶可能在多种癌症类型中广泛失调。在此，我们发现对这两种酶的药理学阻断会损害多种不同类型癌细胞（包括乳腺癌、卵巢癌、黑色素瘤和前列腺癌）的致癌性。我们还表明，对PAFAH1B2和1B3的药理学阻断会导致脂质代谢发生独特变化，包括抑癌脂质水平升高。我们的结果利用基于活性的蛋白质谱分析揭示了几种与癌症相关的丝氨酸水解酶的致癌调控机制，并且我们表明PAFAH1B2和1B3在维持广泛癌症类型的致癌性方面很重要。
