Signal Transduction Pathways Involved in PPARβ/δ-Induced Neuronal Differentiation

Neuroblastomas are pediatric tumors originating from neuroblasts in the developing peripheral nervous system. The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of survival and differentiation of specific neuronal populations in the central and peripheral nervous system. Patients whose neuroblastoma tumors express high levels of BDNF and TrkB have an unfavorable prognosis. We have previously reported on the neuronal differentiating activity of peroxisome proliferator-activated receptors (PPAR)beta/delta natural and synthetic ligands by modulating BDNF/TrkB pathway, suggesting their potential use as new therapeutic strategies for neuroblastoma. The validation of new therapeutic agents implies the understanding of their mechanisms of action. Herein, we report the effects of activated-PPAR beta/delta on signal transduction pathways known to be involved in neuronal differentiation, such as ERK1,2 and BDNF pathways. The results obtained, using also PPAR beta/delta silencing, indicating a neuronal differentiating effect PPAR beta/delta-dependent through BDNF-P75-ERK1,2 pathways, further support a role for PPAR beta/delta in neuronal differentiation and pointing towards PPAR beta/delta as a modulator of pathways crucial for neuronal differentiation. These findings open new perspectives in the formulation of potential therapeutic approaches to be used as adjuvant treatment with the standard therapies. J. Cell. Physiol. 226: 2170-2180, 2011. (C) 2010 Wiley-Liss, Inc.