Inhibition of the Peptidyl-Prolyl-Isomerase Pin1 Enhances the Responses of Acute Myeloid Leukemia Cells to Retinoic Acid via Stabilization of RAR and PML-RAR

^{1 1}Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy; ²Division of Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy; ³Department of Functional Genomics, Institut de Genetique et Biologie Moleculaire, Illkirch, France; and ⁴Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, Università di Trieste; Dipartimento di Biochimica Biofisica e Chimica delle Macromolecole, Trieste, Italy

^* To whom correspondence should be addressed. E-mail: egarattini{at}marionegri.it.

	Abstract

The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RAR and the acute-promyelocytic-leukemia–specific counterpart PML-RAR directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RAR and PML-RAR. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein–binding activity are incapable of inhibiting ligand-dependent RAR transcriptional activity. Functional inhibition of RAR and PML-RAR by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RAR in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RAR and PML-RAR, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids. [Cancer Res 2009;69(3):1016–26

Key Words: retinoic acid, acute myeloid leukemia, Pin1, differentiation, experimental therapeutics, RAR

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