title: AKR1C isoforms represent a novel cellular target for jasmonates alongside their mitochondrial-mediated effects.
abstract: Members of the aldo-keto reductase (AKR) superfamily, particularly the AKR1C subfamily, are emerging as important mediators of the pathology of cancer. Agents that inhibit these enzymes may provide novel agents for either the chemoprevention or treatment of diverse malignancies. Recently, jasmonates, a family of plant stress hormones that bear a structural resemblance to prostaglandins, have been shown to elicit anticancer activities both in vitro and in vivo. In this study, we show that jasmonic acid (JA) and methyl jasmonate (MeJ) are capable of inhibiting all four human AKR1C isoforms. Although JA is the more potent inhibitor of recombinant AKR1C proteins, including the in vitro prostaglandin F synthase activity of AKR1C3, MeJ displayed greater potency in cellular systems that was, at least in part, due to increased cellular uptake of MeJ. Moreover, using the acute myelogenous leukemia cell lines HL-60 and KG1a, we found that although both jasmonates were able to induce high levels of reactive oxygen species in a dose-dependent fashion, only MeJ was able to induce high levels of mitochondrial superoxide (MSO), possibly as an epiphenomenon of mitochondrial damage. There was a strong correlation observed between MSO formation at 24 hours and reduced cellularity at day 5. In conclusion, we have identified AKR1C isoforms as a novel target of jasmonates in cancer cells and provide further evidence of the promise of these compounds, or derivatives thereof, as adjunctive therapies in the treatment of cancer.
authors.affiliation: College of Life and Environmental Sciences, School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Davies
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Hayden
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Simpson
authors.forename: Jane
authors.initials: J
authors.lastname: Birtwistle
authors.forename: Katarina
authors.initials: K
authors.lastname: Mayer
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Ride
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bunce
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008954:Models, Biological; D054883:Oxylipins / Q000493:pharmacokinetics / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000085:Acetates; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054883:Oxylipins; D017382:Reactive Oxygen Species; C011006:jasmonic acid; C072239:methyl jasmonate; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D006911:Hydroxyprostaglandin Dehydrogenases; C031051:prostaglandin-F synthase; D015230:Prostaglandin D2