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Carcinogenesis Advance Access originally published online on December 4, 2008
Carcinogenesis 2009 30(2):230-237; 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,{dagger}, Claudia Gemelli1,2,{dagger}, Anna Testa1, Giulia Facchini1, Francesco Ferrari1,3, Fulvio Mavilio1 and Alexis Grande1,*

1 Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy
2 Ergentech laboratory of genetics and biotechnology
3 Department of Biology, University of Padova, Padova 35121, Italy

* To whom correspondence should be addressed. 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; Email: alexis.grande{at}unimore.it

A number of reports indicate that peroxisome proliferator-activated receptor (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 overexpression 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 co-operated with VD treatment. In spite of this, PPAR{delta} overexpression 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 (AMLs). Bioinformatic analysis of a microarray database, containing the expression profiles of 285 AML cases, further supported this hypothesis demonstrating the existence of a subset of M5 type (monoblastic) AMLs that overexpress PPAR{delta} gene.

Abbreviations: AA, arachidonic acid; AML, acute myeloid leukemia; cDNA, complementary DNA; cPGI, carbaprostacyclin; FAB, French-American-British classification; mRNA, messenger RNA; NGFR, nerve growth factor receptor; PCR, polymerase chain reaction; PMA, phorbol l2-myristate l3-acetate; PPAR, peroxisome proliferator-activated receptor; QRT, quantitative reverse transcription; RT, reverse transcription; siRNA, small interference RNA; VD, 1{alpha},25-dihydroxyvitamin D3; VDR, vitamin D receptor

{dagger} These authors contributed equally to this work.

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


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