Abstract
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.
Highlights
The expression of nuclear progesterone receptor is needed for cell proliferation and maturation of breast tissue, and further, nPR expression is found under the regulation of the estrogens [1]
These negative effects in MDA-MB-231 cells are suggested to be mediated by membrane progesterone α [7], which might be modulated by progesterone receptor membrane component 1 (PGRMC1) [1]
In MDA-MB-231 cells, we demonstrated that inhibition of sigma-2R with NO1 reported a different effect on TG-evoked store-operated Ca2+ entry (SOCE) to the one presented here by silencing Progesterone receptor membrane component 1 (PGRMC1) [26]
Summary
The expression of nuclear progesterone receptor (nPR) is needed for cell proliferation and maturation of breast tissue, and further, nPR expression is found under the regulation of the estrogens [1]. The effect of P4 on cell proliferation has been described depending on nPR activation; the triple-negative breast cancer (TNBC) cell lines should remain unaltered in the presence of P4; recent studies have claimed that P4 evokes alteration of the TNBC cells [7,8]. These negative effects in MDA-MB-231 cells are suggested to be mediated by membrane progesterone α (mPRα) [7], which might be modulated by progesterone receptor membrane component 1 (PGRMC1) [1]. More recent studies have been performed to identify alternative P4 receptors, leading to the identification of two additional protein families that are able to transduce the P4 effects in the neuroimmune system and other tissues [10,11]: (1) Class II progestin and adipoQ receptor family members (PAQR) (such as mPRα is known as PAQR7)); (2) B5-like heme/steroid-binding protein family that groups proteins like the PGRMC1,PGRMC2, and others [10]
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