AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects
AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects
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DOI：
10.1158/0008-5472.can-08-4533
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Bunce, Chris M.
中科院分区：
文献类型：
--
作者：
Davies, Nicholas J.;Hayden, Rachel E.;Bunce, Chris M.
醛酮还原酶（AKR）超家族成员，特别是AKR 1C亚家族，正在成为癌症病理学的重要介质。抑制这些酶的药剂可提供用于多种恶性肿瘤的化学预防或治疗的新药剂。最近，茉莉酸酯，一个家庭的植物应激激素，承担的结构相似的野牡丹素，已被证明在体外和体内引起抗癌活性。在这项研究中，我们表明，茉莉酸（JA）和茉莉酸甲酯（MeJ）能够抑制所有四种人类AKR 1C亚型。尽管Mej是重组AKR 1C蛋白的更有效的抑制剂，包括AKR 1C 3的体外前列腺素F合酶活性，但Mej在细胞系统中显示出更大的效力，这至少部分是由于Mej的细胞摄取增加。此外，使用急性髓性白血病细胞系HL-60和KG 1a，我们发现，尽管两种茉莉酸酯都能够以剂量依赖性方式诱导高水平的活性氧，但只有茉莉酸酯能够诱导高水平的线粒体超氧化物（MSO），这可能是线粒体损伤的附带现象。在24小时的MSO形成和第5天的细胞结构减少之间观察到强相关性。总之，我们已经鉴定了AKR 1C同种型作为癌细胞中茉莉酸酯的新靶点，并提供了这些化合物或其衍生物作为癌症治疗中的连续疗法的前景的进一步证据。[Cancer Res 2009;69（11）：4769-75]
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)A 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 Me) 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. [Cancer Res 2009;69(11):4769-75]