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

Abstract

The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO/H chemosensitivity. The recovery of CO/H chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin 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, and evaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on the expression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear receptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and its target genes and open up the possibility that this mechanism may contribute to the positive effects observed in some CCHS patients.

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

“…Data reported in Cardani et al (2018) also showed that a slight PHOX2B decrease does not cause a down-regulation of all PHOX2B target genes, and in cell lines expressing PHOX2A and low levels of PHOX2B, progesterone may have the paradoxical effect of inducing tyrosine hydroxylase (Jensik and Arbogast, 2011), a well-known PHOX2B target gene. These findings suggest that PHOX2B expression level and the targeted cell-type may determine the positive or negative progesterone-mediated effects.…”

“…Progesterone induces both genomic and non-genomic effects (Singh et al, 2013;Stanczyk et al, 2013;Schumacher et al, 2014) by the activation of nuclear (PGR) or membrane (mPR) receptors (Brinton et al, 2008;Figure 4); it has been shown that both receptors have a role in the modulation of chemoreflex response and respiratory control particularly during sleep (Bairam et al, 2019, and references therein). The exact molecular mechanism underlying this pharmacological effect is unknown; recently, in vitro studies showed that PHOX2B and desogestrel are molecularly linked demonstrating that the biologically active metabolite of desogestrel, 3-Ketodesogestrel (3-KDG; etonogestrel, ETO), modulates both wild type and mutant PHOX2B and the expression of its target genes via progesterone nuclear receptor PR-B (PGR) (Cardani et al, 2018). Remarkably, the expression of both wild-type and mutated PHOX2B is negatively regulated by 3-KDG (Figure 4).…”

“…After P4 binding, it form dimers, translocates to the nucleus and dimers bind to Progesterone Responsive Element (PRE) within gene promoters and regulate the expression of target genes. The scheme also shows that the activation of PGR receptor by ETO is able to induce PHOX2B down-regulation by unknown mechanisms(Cardani et al, 2018), with possible effects on the expression of some PHOX2B target genes. Non-genomic effects of P4/ETO are mediated by the binding of P4 to cognate membrane receptors (mPR and PGRMC1) or to those belonging to other neurotransmitters (such as GABA A receptors).…”

Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)

“…Within the CNS-PNET samples, 44 CNS-NB samples were found to overexpress FOXR2 and thus categorized as “CNS NB-FOXR2” [45]. Interestingly, FOXR1 has been previously found to be overexpressed in peripheral neuroblastoma [45] and PHOX2B mutations have been recently described in NB as a potential target for therapy [46,47].…”

Neurogenesis From Neural Crest Cells: Molecular Mechanisms in the Formation of Cranial Nerves and Ganglia

“…In humans, PHOX2B over-expression has been linked to the formation of tumors arising from the sympathetic nervous system such as neuroblastomas. Heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome, a life-threatening neurocristopathy characterized by the defective autonomic control of breathing and involving altered CO 2 /H + chemosensivity (Cardani et al, 2018;Vega-Lopez et al, 2018).…”