title: Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer.
abstract: 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.
authors.affiliation: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, California 94720, United States.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Kohnz
authors.affiliation: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, California 94720, United States.
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Mulvihill
authors.affiliation: ‡Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR107, La Jolla, California 92037, United States.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: §Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, Virginia 22904-4319, United States.
authors.forename: Ku-Lung
authors.initials: KL
authors.lastname: Hsu
authors.forename: Antonio
authors.initials: A
authors.lastname: Sorrentino
authors.affiliation: ‡Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Rd. SR107, La Jolla, California 92037, United States.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: #University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, Box 0128, San Francisco, California 94143, United States.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: †Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, California 94720, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*
chemical_list: D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C523923:PAFAH1B2 protein, human; C568468:PAFAH1B3 protein, human