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.

Methyl jasmonate enhances the radiation sensitivity of esophageal carcinoma cells by inhibiting the 11-ketoprostaglandin reductase activity of <em>AKR1C3</em>

“…These results showed that the radiation sensitivity effects of MeJ depended upon the expression of AKR1C3 . MeJ can inhibit the 11-keto-prostaglandin reductase activity of AKR1C3 and decrease PGF2 10. In our study, we showed that MeJ decreased the PGF2 content of KY170R cells while increasing PGD2.…”

“…Based on our previous studies,8,9 we wanted to find an inhibitor target related to the prostaglandin metabolism of AKR1C3 , which would also be capable of increasing cellular ROS levels. Methyl jasmonate (MeJ) was an effective small molecule inhibitor of the PGD2 11-keto reductase activity of the AKR1C3 enzyme 10. MeJ also increased ROS levels in many types of human cancer cells 10–12.…”

“…Methyl jasmonate (MeJ) was an effective small molecule inhibitor of the PGD2 11-keto reductase activity of the AKR1C3 enzyme 10. MeJ also increased ROS levels in many types of human cancer cells 10–12. Therefore, in this study we wanted to investigate whether MeJ could increase the radiation sensitivity of KY170R cells.…”

Human Metabolic Individuality in Biomedical and Pharmaceutical Research

“…Moreover, systematic inclusion of biochemically relevant GDMs as candidate SNPs during drug trials may permit early identification of potentially adverse pharmacogenetic effects. Concretely this applies to AKR1C, which is a novel target of jasmonates in cancer cells 31 . We reported a GDM associated with AKR1C with a large effect size on androgen metabolism.…”

Polymer Monolith Microextraction Coupled with HPLC for Determination of Jasmonates in Wintersweet Flowers

“…Jasmonates were found to induce suppression of cellular proliferation and death in various cell lines and could suppress the proliferation or kill various other cancer cells. Selective cytotoxicity toward cancer cells was also observed and jasmonates also had some effects on apoptosis (Devies et al 2009;Fingrut and Flescher 2002;Flescher 2005;Ishii et al 2004; J. H. Kim et al 2004;Kniazhanski et al 2008;Xiao et al 2011a).…”