Desogestrel down-regulates PHOX2B and its target genes in progesterone responsive neuroblastoma cells

The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the de-velopment of the autonomic nervous system and the neural structures involved in controlling breathing. Inhumans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympatheticnervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital CentralHypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective auto-nomic control of breathing and involving altered CO2/H+chemosensitivity. The recovery of CO2/H+chemo-sensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptiveprogestin desogestrel. Given the central role of PHOX2B in the pathogenesis of CCHS, and the progesterone-mediated effects observed in the disease, we generated progesterone-responsive neuroblastoma cells, andevaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on theexpression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear re-ceptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and itstarget genes and open up the possibility that this mechanism may contribute to the positive effects observed insome CCHS patients.