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Título

Identification of Aldo-keto reductase AKR1B10 as a selective target for modification and inhibition by prostaglandin A1: Implications for anti-tumoral activity

AutorDíez-Dacal, Beatriz CSIC; Gayarre, Javier CSIC ORCID; Gharbi, Severine; Timms, John F.; Coderch, Claire; Gago, Federico CSIC ORCID; Pérez-Sala, Dolores CSIC ORCID
Fecha de publicación15-jun-2011
EditorAmerican Association for Cancer Research
CitaciónCancer Research 71:4161-4171(2011)
ResumenCyclopentenone 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 A1 (PGA1). 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 PGA1 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 PGA1 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 PGA1 (PGA1-B) in cells, and confirmed that mutation of Cys299 abolishes PGA1-B incorporation, whereas substitution of His111 or Tyr49 reduced the interaction. Modification of AKR1B10 by PGA1 correlated with loss of enzymatic activity and both effects were increased by depletion of cellular glutathione. Moreover, in lung cancer cells PGA1 reduced tumorigenic potential and increased accumulation of the AKR substrate doxorubicin, potentiating cell-cycle arrest induced by this hemotherapeutic agent. Our findings define PGA1 as a new AKR inhibitor and they offer a framework to develop compounds that could counteract cancer chemoresistance
Descripción11 páginas, 6 figuras -- PAGS nros. 4161-4171
Versión del editorhttp://dx.doi.org/10.1158/0008-5472.CAN-10-3816
URIhttp://hdl.handle.net/10261/51641
DOI10.1158/0008-5472.CAN-10-3816
ISSN0008-5472
E-ISSN1538-7445
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