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Papers In Press, published online ahead of print July 28, 2004
Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, MI 20157
Corresponding Author: egarattini{at}marionegri.it
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), RARa or RXR 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 RXR agonists. Treatement of NB4 cells with piclamilast or ATRA results in activation of the cAMP signaling pathway and nuclear translocation of cAMP-dependent protein kinase (PKA). This causes a transitory increase in CREB 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 RARa through a PKA-dependent phosphorylation. Enhanced transactivation is also observed in the case of PML-RARa. 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 cyto-differentiation. Finally, ERK kinase and the cAMP-target protein, Epac, do not participate in the maturation program activated by ATRA+piclamilast. Initial in vivo studies conducted in SCID mice transplanted with NB4 leukemia cells indicate that the enhancing effect of piclamilast on ATRA induced myeloid maturation translates into a therapeutic benefit.
J. Biol. Chem, 10.1074/jbc.M406530200
Submitted on June 11, 2004
Revised on July 20, 2004
Accepted on July 28, 2004
Phosphodiesterase IV inhibition by piclamilast potentiates the cyto-differentiating action of retinoids in myeloid leukemia cells: Cross-talk between the cAMP and the retinoic acid signaling pathways
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