An Enzyme that Regulates Ether Lipid Signaling Pathways in Cancer Annotated by Multidimensional Profiling

Abstract

Hundreds, if not thousands, of uncharacterized enzymes currently populate the human proteome. Assembly of these proteins into the metabolic and signaling pathways that govern cell physiology and pathology constitutes a grand experimental challenge. Here, we address this problem by using a multidimensional profiling strategy that combines activity-based proteomics and metabolomics. This approach determined that KIAA1363, an uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and lysophosphatidic acid. Biochemical studies confirmed that KIAA1363 regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of KIAA1363 disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo. The integrated molecular profiling method described herein should facilitate the functional annotation of metabolic enzymes in any living system.

Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

“…For example, we have reported that monacylglycerol lipase is up-regulated across aggressive cancer cells and primary tumors where it controls release of FFAs from monoacylglycerols to fuel generation of FFA-derived oncogenic signaling lipids, such as LPA and PGE2 to drive malignant features of cancer (18). Chiang et al demonstrated that blocking of KIAA1363, a deacetylase of 2-acetyl MAGe, lowers levels of its neutral ether lipid product MAGe, which decreases the levels of its downstream metabolite LPAe, leading to impaired cellular migration and tumor growth (15). It will be of future interest to determine the effects of polypharmacologically blocking several of these pathways simultaneously in cancer cells to achieve maximal anticancer activity.…”

“…The physiological roles of ether lipids are not well understood, but they have been implicated in maintaining physicochemical properties of cell membranes, such as membrane fluidity, membrane fusion events, and lipid raft microdomains (9,10). Certain ether lipids, such as lysophosphatidic acid-ether (LPAe) or platelet-activating factor-ether (PAFe), are signaling molecules that have been shown to possess bioactive and even oncogenic properties through binding specific receptors (11)(12)(13)(14)(15). In the late 1960s, Snyder and Wood first reported that rodent and human tumors possess significantly higher levels of ether lipids relative to normal tissue.…”

Application of activity-based probes to the study of enzymes involved in cancer progression

“…Since cathepsin B is suspected of facilitating tumor invasion, this compound could potentially be used as a lead target for cancer therapy. ABP-based assays using the serine hydrolase probe FP-rhodamine have also been applied to the discovery of novel, selective inhibitors of KIAA1363, a poorly characterized enzyme with highly elevated activity in invasive cancer cells [34,35]. This screen yielded valuable lead compounds that facilitated further study of the function of KIAA1363 in the metabolism of lipids.…”

RBBP9: A tumor-associated serine hydrolase activity required for pancreatic neoplasia

“…Recent studies have demonstrated that serine hydrolase ABPP permits the classification of human cancer lines into functional subtypes on the basis of tissue of origin and state of invasiveness (3). Moreover, this approach has identified tumor-associated activities with roles in cell invasion, migration, and intravasation (1,3,4).…”

“…functional proteomics | activity profiling | pancreatic cancer TGF-β signaling S erine hydrolases are central effectors of the proliferative, invasive, and migratory properties of tumors, with roles in growth factor activation, extracellular matrix degradation, and angiogenesis (1)(2)(3)(4). Serine hydrolase transcript and protein levels are elevated in many cancer cell lines and primary tumors, but the functional relevance of these changes remains unknown (3,5).…”