The Role of mPRδ and mPRε in Human Glioblastoma Cells: Expression, Hormonal Regulation, and Possible Clinical Outcome

Glioblastomas (GBM) are the most frequent and aggressive primary tumor of the central nervous system. In recent years, it has been proposed that sex hormones such as progesterone play an essential role in GBM biology. Membrane progesterone receptors (mPRs) are a group of G protein-coupled receptors with a wide distribution and multiple functions in the organism. There are five mPRs subtypes described in humans: mPRalpha, mPRbeta, mPRgamma, mPRdelta, and mPRepsilon. It has been reported that human-derived GBM cells express the mPRalpha, mPRbeta, and mPRgamma subtypes, and that progesterone promotes GBM progression in part by mPRalpha specific activation; however, it is still unknown if mPRdelta and mPRepsilon are also expressed in this type of tumor cells. In this study, we characterized the expression and hormonal regulation of mPRdelta and mPRepsilon in human GBM cells. We also analyzed a set of biopsies from TCGA. We found that the expression of these receptors is dependent on the tumor's grade and that mPRdelta expression is directly correlated to patients' survival while the opposite is observed for mPRepsilon. By RT-qPCR, Western blot, and immunofluorescence, the expression of mPRdelta and mPRepsilon was detected for the first time in human GBM cells. An in silico analysis showed possible progesterone response elements in the promoter regions of mPRdelta and mPRepsilon, and progesterone treatments downregulated the expression of these receptors. Our results suggest that mPRdelta and mPRepsilon are expressed in human GBM cells and that they are relevant to GBM biology.