title: Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) is among the top ten most common forms of cancer and is the most common malignancy of the kidney. Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory cancers with an incidence that is on the rise. Screening of plant extracts in search of new anti-cancer agents resulted in the discovery of englerin A, a guaiane sesquiterpene with potent cytotoxicity against renal cancer cells and a small subset of other cancer cells. Though a few cellular targets have been identified for englerin A, it is still not clear what mechanisms account for the cytotoxicity of englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of englerin A. Metabolomics analyses indicated that englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of ceramides that were highly toxic to these cells. Microarray analyses determined that englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other lipid storing cancers. Furthermore, our results suggest that ceramides may be a mediator of some of the actions of englerin A. Lastly, the acute inflammatory response induced by englerin A may mediate anti-tumor immunity.
authors.affiliation: Department of Pediatrics, University of California, San Diego, California, United States of America.
authors.forename: Ayse
authors.initials: A
authors.lastname: Batova
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.
authors.forename: Diego
authors.initials: D
authors.lastname: Altomare
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Creek
authors.affiliation: Department of Pediatrics, University of California, San Diego, California, United States of America.|The Mitochondrial and Metabolic Disease Center, Department of Pathology, University of California, San Diego, San Diego, California, United States of America.|Department of Medicine, University of California, San Diego, California, United States of America.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Naviaux
authors.affiliation: The Mitochondrial and Metabolic Disease Center, Department of Pathology, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Mitochondrial and Metabolic Disease Center, Department of Pathology, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.
authors.forename: Erica
authors.initials: E
authors.lastname: Green
authors.affiliation: Department of Pediatrics, University of California, San Diego, California, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.affiliation: The Mitochondrial and Metabolic Disease Center, Department of Pathology, University of California, San Diego, San Diego, California, United States of America.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Naviaux
authors.affiliation: Department of Pediatrics, University of California, San Diego, California, United States of America.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Diccianni
authors.affiliation: Department of Pediatrics, University of California, San Diego, California, United States of America.|Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects*; D045789:Sesquiterpenes, Guaiane / Q000494:pharmacology*
chemical_list: D045789:Sesquiterpenes, Guaiane; C534971:englerin A