Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARα and PML-RARα

Maurizio Gianni', Andrea Boldetti, Valeria Guarnaccia, Alessandro Rambaldi, Edoardo Parrella, Ivan Raska, Cecile Rochette-Egly, Giannino Del Sal, Alessandra Rustighi, Mineko Terao, Enrico Garattini

Research output: Contribution to journalArticlepeer-review

Abstract

The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARα and the acute-promyelocytic-leukemia-specific counterpart PML-RARα directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARα and PML-RARα. 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 RARα transcriptional activity. Functional inhibition of RARα and PML-RARα 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 RARα in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARα and PML-RARα, 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.

Original languageEnglish
Pages (from-to)1016-1026
Number of pages11
JournalCancer Research
Volume69
Issue number3
DOIs
Publication statusPublished - Feb 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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