Identification of Aldo-Keto Reductase AKR1B10 as a Selective Target for Modification and Inhibition by Prostaglandin A1: Implications for Antitumoral Activity
Identification of Aldo-Keto Reductase AKR1B10 as a Selective Target for Modification and Inhibition by Prostaglandin A1: Implications for Antitumoral Activity
复制标题
DOI：
10.1158/0008-5472.can-10-3816
复制
发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Perez-Sala, Dolores
中科院分区：
文献类型：
--
作者：
Diez-Dacal, Beatriz;Gayarre, Javier;Perez-Sala, Dolores
环戊烯酮类胡萝卜素（Cyclopentenone elephandins，cyPG）是一种具有抗炎和抗增殖作用的活性类花生酸，具有潜在的治疗作用。在这里，我们报告了醛酮还原酶（AKR）家族成员作为cyPG前列腺素A（1）（PGA（1））的选择性靶点的鉴定。AKR酶代谢醛和含有羰基的药物，并参与炎症和肿瘤发生。因此，这些酶代表了开发具有治疗活性的小分子抑制剂的一类靶标。分子模拟研究指出，PGA（1）与Cys 299共价结合，靠近AKR的活性位点，His 111和Tyr 49在AKR家族中高度保守，在PGA（1）取向中发挥作用。在AKR酶中，AKR 1B 10被认为是肿瘤标志物，并有助于肿瘤的发展和耐药性。我们在细胞中验证了生物素化PGA（1）（PGA（1）-B）对AKR 1B 10的直接修饰，并证实Cys 299的突变消除了PGA（1）-B掺入，而His 111或Tyr 49的取代降低了相互作用。PGA对AKR 1B 10的修饰（1）与酶活性的丧失相关，并且细胞谷胱甘肽的消耗增加了这两种作用。此外，在肺癌细胞中，PGA（1）降低了致瘤潜力，增加了AKR底物阿霉素的积累，增强了这种化疗药物诱导的细胞周期停滞。我们的研究结果将PGA（1）定义为一种新的AKR抑制剂，并为开发可以抵消癌症耐药性的化合物提供了一个框架。Cancer Res; 71（12）; 4161-71.（C）2011年《非洲标准化评论》。
Cyclopentenone prostaglandins (cyPG) are reactive eicosanoids that may display anti-inflammatory and antiproliferative actions, possibly offering therapeutic potential. Here we report the identification of members of the aldo-keto reductase (AKR) family as selective targets of the cyPG prostaglandin A(1) (PGA(1)). AKR enzymes metabolize aldehydes and drugs containing carbonyl groups and are involved in inflammation and tumorigenesis. Thus, these enzymes represent a class of targets to develop small molecule inhibitors with therapeutic activity. Molecular modeling studies pointed to the covalent binding of PGA(1) to Cys299, close to the active site of AKR, with His111 and Tyr49, which are highly conserved in the AKR family, playing a role in PGA(1) orientation. Among AKR enzymes, AKR1B10 is considered as a tumor marker and contributes to tumor development and chemoresistance. We validated the direct modification of AKR1B10 by biotinylated PGA(1) (PGA(1)-B) in cells, and confirmed that mutation of Cys299 abolishes PGA(1)-B incorporation, whereas substitution of His111 or Tyr49 reduced the interaction. Modification of AKR1B10 by PGA(1) correlated with loss of enzymatic activity and both effects were increased by depletion of cellular glutathione. Moreover, in lung cancer cells PGA(1) reduced tumorigenic potential and increased accumulation of the AKR substrate doxorubicin, potentiating cell-cycle arrest induced by this chemotherapeutic agent. Our findings define PGA(1) as a new AKR inhibitor and they offer a framework to develop compounds that could counteract cancer chemoresistance. Cancer Res; 71(12); 4161-71. (C)2011 AACR.