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The Aldo-Keto Reductase AKR1C3 Is a Novel Suppressor of Cell Differentiation That Provides a Plausible Target for the Non-Cyclooxygenase-dependent Antineoplastic Actions of Nonsteroidal Anti-Inflammatory Drugs¹

Division of Medical Sciences [J. C. D., J. C. M., E. A. W., M. H.], Division of Immunity and Infection [M. T. D.], and School of Biosciences [J. P. R., Q. T. L., R. E. H., C. M. B.], University of Birmingham, Birmingham, B15 2TH United Kingdom, and Division of Experimental Hematology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105 [E. F. V.]

We and others have demonstrated expression of the aldo-keto reductase AKR1C3 in myeloid leukemia cell lines and that inhibitors of the enzyme, including nonsteroidal anti-inflammatory drugs (NSAIDs), promote HL-60 differentiation in response to all-trans retinoic acid (ATRA) and 1,25-dihydroxyvitamin D₃ (D₃). Here, we demonstrate that overexpression of AKR1C3 reciprocally desensitizes HL-60 cells to ATRA and D₃, thus confirming the enzyme as a novel regulator of cell differentiation. AKR1C3 possesses marked 11-ketoreductase activity converting prostaglandin (PG) D₂ to PGF₂. Supplementing HL-60 cultures with PGD₂ mimicked treatment with AKR1C3-inhibitors by enhancing the differentiation of the cells in response to ATRA. However, PGD₂ is chemically unstable, being converted first to PGJ₂ and then stepwise to 15-deoxy-^12,14-prostaglandin J₂(15-PGJ₂), a natural ligand for the peroxisome proliferator-activated receptor- (PPAR). Consistent with this, PGD₂ was rapidly converted to PGJ₂ under normal tissue culture conditions but not in the presence of recombinant AKR1C3 when PGF₂ was predominantly formed. In addition, PGJ₂ but not PGF₂ recapitulated the potentiation of HL-60 differentiation by PGD₂ and AKR1C3 inhibitors. Furthermore, the capacity of all of these treatments to potentiate HL-60 cell differentiation was significantly reduced in the presence of the PPAR-antagonist GW 9662. We conclude that AKRIC3 protects HL-60 cells against ATRA and D₃-induced cell differentiation by limiting the production of natural PPAR ligands via the diversion of PGD₂ toward PGF₂ and away from PGJ₂. In addition, these observations identify AKR1C3 as plausible target for the non-cyclooxygenase-dependent antineoplastic actions of NSAIDs.

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