title: Identification of aldo-keto reductase AKR1B10 as a selective target for modification and inhibition by prostaglandin A(1): implications for antitumoral activity.
abstract: 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.
authors.affiliation: Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Díez-Dacal
authors.forename: Javier
authors.initials: J
authors.lastname: Gayarre
authors.forename: Severine
authors.initials: S
authors.lastname: Gharbi
authors.forename: John F
authors.initials: JF
authors.lastname: Timms
authors.forename: Claire
authors.initials: C
authors.lastname: Coderch
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Dolores
authors.initials: D
authors.lastname: Pérez-Sala
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000074408:Aldo-Keto Reductases; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011454:Prostaglandins A / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011454:Prostaglandins A; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C100573:prostaglandin A1