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Carcinogenesis Advance Access published online on December 4, 2008
Carcinogenesis, doi:10.1093/carcin/bgn272
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PPAR{delta} is a ligand dependent negative regulator of Vitamin D3 induced monocyte differentiation

Athina Lymboussaki1, Claudia Gemelli1,2, Anna Testa1, Giulia Facchini1, Francesco Ferrari1,3, Fulvio Mavilio1 and Alexis Grande1,*

1 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
2 Fellow of Ergentech laboratory of genetics and biotechnology
3 Department of Biology, University of Padova, Padova, Italy

* Corresponding author: Alexis Grande, Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena e Reggio Emilia, Via Campi 287, 41100, Modena, Italy; tel. ++39/059/2055409, fax ++39/059/2055410, e-mail: grande{at}unimore.it

A number of reports indicate that peroxisome proliferator activated receptor {delta} (PPAR{delta}) is involved in the molecular control of monocyte – macrophage differentiation. In this regard, the recent demonstration that PPAR{delta} is a primary response gene of 1{alpha}, 25 dihydroxyvitamin D3 (VD), i. e. a powerful inducer of such process, allowed us to hypothesize the existence of a cross - talk between PPAR{delta} and VD receptor pathways. To address this issue we analyzed the effects promoted by stimulation with PPAR{delta} ligands and by over-expression of this nuclear receptor in monoblastic cell lines undergoing exposure to VD. The results obtained evidenced that, although promoting a weak differentiation effect by themselves, PPAR{delta} ligands efficiently cooperated with VD treatment. In spite of this, PPAR{delta} over-expression exerted a remarkable inhibitory effect on monocyte - macrophage differentiation induced by VD that was, at least partly, reverted by stimulation with a highly specific PPAR{delta} ligand. These data indicate that, although acting through a ligand dependent modality, PPAR{delta} is a negative regulator of VD mediated monocyte differentiation, allowing us to hypothesize a role of the investigated nuclear receptor in the differentiation block of M5 type (monoblastic) Acute Myeloid Leukemias (AML). Bioinformatic analysis of a microarray database, containing the expression profiles of 285 AML cases, furtherly supported this hypothesis demonstrating the existence of a subset of M5 type (monoblastic) AMLs that over-express PPAR{delta} gene.

Key Words: Monocyte Differentiation • Peroxisome Proliferator Activated Receptor {delta} • Vitamin D Receptor • Acute Myeloid Leukemias

Received July 1, 2008; revised November 1, 2008; accepted November 29, 2008.


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