Progesterone inhibits apoptosis in part by PGRMC1-regulated gene expression

Abstract

Progesterone Receptor Membrane Component-1 (PGRMC1) is present in both the cytoplasm and nucleus of spontaneously immortalized granulosa cells (SIGCs). PGRMC1 is detected as a monomer in the cytoplasm and a DTT-resistant PGRMC1 dimer in the nucleus. Transfected PGRMC1-GFP localizes mainly to the cytoplasm and does not form a DTT-resistant dimer. Moreover, forced expression of PGRMC1-GFP increases the sensitivity of the SIGCs to progesterone (P4) 's antiapoptotic action, indicating that the PGRMC1 monomer is functional. However, when endogenous PGRMC1 is depleted by siRNA treatment and replaced with PGRMC1-GFP, P4 responsiveness is not enhanced, although overall levels of PGRMC1 are increased. P4's anti-apoptotic action is also attenuated by actinomycin D, an inhibitor of RNA synthesis, and P4 activation of PGRMC1 suppresses Bad and increases Bcl2a1d expression. Taken together, the present studies suggest a genomic component to PGRMC1's anti-apoptotic mechanism of action, which requires the presence of the PGRMC1 dimer.

Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

“…3B, C). It was also of interest to determine if P4 suppressed stressinduced apoptosis of breast cancer cells and whether or not PGRMC1 mediates the anti-apoptotic actions of P4 as has been shown in granulosa cells, 35 as well as ovarian 26,36 and endometrial cancer cells. 29 While P4 treatment did not change basal apoptosis (»5%) of PGRMC1-intact MDA cells, the chemotherapeutic agent doxorubicin (Dox) increased apoptosis to 32% after 48 h of treatment (p 0.05, Fig.…”

The role of BH3-only proteins in apoptosis within the ovary

“…Instead, induction of granulosa cell apoptosis by loss of hormonal support is associated with the activation of BAD through its dephosphorylation, (Kaipia et al 1997, Gebauer et al 1999. More recent work has provided additional support for the involvement of BAD in granulosa cells apoptosis by showing that progesterone suppresses granulosa cell apoptosis by binding the progesterone receptor BH3-only proteins regulate apoptosis in the ovary R85 membrane component-1 (PGRMC1) and inhibiting BAD gene expression (Peluso et al 2010;reviewed in Peluso (2013)). In addition, one of the mechanisms by which VEGFA is thought to promote granulosa cell survival is through its ability to increase AKT-mediated phosphorylation of BAD (Abramovich et al 2010).…”

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

“…However, whether the sigma-2 receptor and PGRMC1 are one in the same molecule remains controversial (Abate et al, 2015;Chu et al, 2015). Furthermore, the physiologic effects of PGRMC1 activation have largely been shown to promote cell survival and inhibit apoptosis, which is in direct contrast to classic proapoptotic models of sigma-2 receptor activation (Lösel et al, 2008;Neubauer et al, 2009;Ahmed et al, 2010;Peluso et al, 2010). Interestingly, activation of PGRMC1 by cell-impermeable progesterone was shown to significantly stimulate VEGF gene expression in MCF-7 cells (Neubauer et al, 2009).…”