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J. Biol. Chem., Vol. 279, Issue 40, 42026-42040, October 1, 2004

This Article Full Text Full Text (PDF) Suplemental Data All Versions of this Article: 279/40/42026    most recent M406530200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Parrella, E. Articles by Garattini, E. Search for Related Content PubMed PubMed Citation Articles by Parrella, E. Articles by Garattini, E. Social Bookmarking                      What's this?

Phosphodiesterase IV Inhibition by Piclamilast Potentiates the Cytodifferentiating Action of Retinoids in Myeloid Leukemia Cells

CROSS-TALK BETWEEN THE cAMP AND THE RETINOIC ACID SIGNALING PATHWAYS^*

Edoardo Parrella, Maurizio Gianni', Virginia Cecconi, Elisa Nigro, Maria Monica Barzago, Alessandro Rambaldi, Cecile Rochette-Egly¶, Mineko Terao, and Enrico Garattini||

From the Laboratory of Molecular Biology, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, Milano 20157, Italy, the Division of Hematology, Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo 24100, Italy, and ^¶Institut de Genetique et Biologie Moleculaire, 67404 Illkirch, France

Inhibition of phosphodiesterase IV by N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (piclamilast) enhances the myeloid differentiation induced by all-trans-retinoic acid (ATRA), retinoic acid receptor (RAR), or retinoic acid receptor X agonists in NB4 and other retinoid-sensitive myeloid leukemia cell types. ATRA-resistant NB4.R2 cells are also partially responsive to the action of piclamilast and retinoic acid receptor X agonists. Treatment of NB4 cells with piclamilast or ATRA results in activation of the cAMP signaling pathway and nuclear translocation of cAMP-dependent protein kinase. This causes a transitory increase in cAMP-responsive element-binding protein phosphorylation, which is followed by down-modulation of the system. ATRA + piclamilast have no additive effects on the modulation of the cAMP pathway, and the combination has complex effects on cAMP-regulated genes. Piclamilast potentiates the ligand-dependent transactivation and degradation of RAR through a cAMP-dependent protein kinase-dependent phosphorylation. Enhanced transactivation is also observed in the case of PML-RAR. In NB4 cells, increased transactivation is likely to be at the basis of enhanced myeloid maturation and enhanced expression of many retinoid-dependent genes. Piclamilast and/or ATRA exert major effects on the expression of cEBP and STAT1, two types of transcription factors involved in myeloid maturation. Induction and activation of STAT1 correlates directly with enhanced cytodifferentiation. Finally, ERK and the cAMP target protein, Epac, do not participate in the maturation program activated by ATRA + piclamilast. Initial in vivo studies conducted in severe combined immunodeficiency mice transplanted with NB4 leukemia cells indicate that the enhancing effect of piclamilast on ATRA-induced myeloid maturation translates into a therapeutic benefit.

Received for publication, June 11, 2004 , and in revised form, July 20, 2004.

^* This work was supported by grants from the Associazione Italiana per la Ricerca contro il Cancro, the "Istituto Superiore di Sanità," the "Progetto Finalizzato Oncologia" (CNR-Ministero dell'Università e della Ricerca Scientifica e Tecnologica), and the "Fondo D'Investimento per la Ricerca Biotecnologica" (to E. G.). This work was also supported by the Weizmann-Pasteur-Negri Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains an additional figure.

^|| To whom correspondence should be addressed. Tel.: 39-02-39014533; Fax: 39-02-3546277; E-mail: egarattini{at}marionegri.it.

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