Thieffry_Supplementary information.pdf
Supplementary information of submitted publication "AG-205 upregulates enzymes involved in cholesterol biosynthesis and steroidogenesis in human endometrial cells independently of PGRMC1 and related MAPR proteins"
Abstract:
Inappropriate
response to progestogens in the human endometrium can result in fertility
issues and jeopardize progestin-based treatments against pathologies such as
endometriosis. PGRMC1 can mediate progesterone response in breast and ovary but
its endometrial functions remain unknown. AG-205 is an alleged PGRMC1 inhibitor
but its specificity was recently questioned. We added AG-205 in cultures of two
endometrial cell lines and performed transcriptomic comparison. AG-205
significantly increased expression of genes coding enzymes of the cholesterol
biosynthetic pathway or of steroidogenesis. However, these observations were
not reproduced with cells transfected with siRNA against PGRMC1 or its related
proteins (MAPRs). Furthermore, AG-205 retained its ability to increase
expression of selected target genes even when expression of PGRMC1 or all MAPRs
was concomitantly downregulated, indicating that neither PGRMC1 nor any MAPR is
required to mediate AG-205 effect. In conclusion, although AG-205 has
attractive effects encouraging its use to develop therapeutic strategies, for
instance against breast cancer, our study delivers two important warning
messages. First, AG-205 is not specific for PGRMC1 or other MAPRs and its
mechanisms of action remain unclear. Second, due to its effects on genes
involved in steroidogenesis, its use may increase the risk for endometrial
pathologies resulting from imbalanced hormones concentrations.