PGRMC1 Inhibits Progesterone-Evoked Proliferation and Ca²⁺ Entry Via STIM2 in MDA-MB-231 Cells.

Progesterone receptor membrane component 1 (PGRMC1) has been shown to regulate some cancer hallmarks. Progesterone (P₄) evokes intracellular calcium (Ca²⁺) changes in the triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468, and BT-20) and in other breast cancer cell lines like the luminal MCF7 cells. PGRMC1 expression is elevated in MDA-MB-231 and MCF7 cells as compared to non-tumoral MCF10A cell line, and PGRMC1 silencing enhances P₄-evoked Ca²⁺ mobilization. Here, we found a new P₄-dependent Ca²⁺ mobilization pathway in MDA-MB-231 cells and other triple-negative breast cancer cells, as well as in MCF7 cells that involved Stromal interaction molecule 2 (STIM2), Calcium release-activated calcium channel protein 1 (Orai1), and Transient Receptor Potential Channel 1 (TRPC1). Stromal interaction molecule 1 (STIM1) was not involved in this novel Ca²⁺ pathway, as evidenced by using siRNA STIM1. PGRMC1 silencing reduced the negative effect of P₄ on cell proliferation and cell death in MDA-MB-231 cells. In line with the latter observation, Nuclear Factor of Activated T-Cells 1 (NFAT1) nuclear accumulation due to P₄ incubation for 48 h was enhanced in cells transfected with the small hairpin siRNA against PGRMC1 (shPGRMC1). These results provide evidence for a novel P₄-evoked Ca²⁺ entry pathway that is downregulated by PGRMC1.

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