Orai1-mediated store-operated Ca2+ entry (SOCE) in breast cancer signaling and entosis

Abstract

The intracellular Ca2+ concentrations are highly regulated by a variety of Ca2+ channels that can be disrupted in cancer. Store-operated Ca2+ entry (SOCE) is a primary source of Ca2+ influx in non-excitable cells, which is activated by the decrease in Ca2+ concentration within the endoplasmic reticulum (ER) in response to cell surface receptor stimulation. SOCE is regulated by the ER membrane protein STIM1 (stromal interaction molecular 1), which translocates to the junctional sites between the ER and plasma membrane (PM) to open the Ca2+ channel Orai1 when sensing a decrease in ER Ca2+ concentration. Any disruption of STIM1 or Orai1 function can have a direct influence on SOCE and potentially affect various pathophysiological activities, such as cancer metastasis, which is accountable for approximately 90% of all cancer-related deaths. Overexpression of progesterone receptor membrane component 1 (PGRMC1) is associated with decreased cancer patient survivability. However, the intracellular signaling pathways involved are largely unknown. Here, we report that PGRMC1 functions as a regulator of store-operated Ca2+ entry (SOCE) by interacting with stromal interaction molecular 1 (STIM1) to promote its conformational switch, leading to the activation of the nuclear factor of the activated T cell (NFAT) pathway. Additionally, genetic depletion of PGRMC1 caused impaired SOCE and disrupted focal adhesion turnover and actomyosin formation in breast cancer cells. These findings indicate that PGRMC1 is essential for regulating Ca2+ signaling in breast cancer cells, providing a potential target for treating cancer metastasis and a greater understanding of the PGRMC1/SOCE-induced biological processes. Additionally, entosis is a non-apoptotic process of cell death that forms characteristic cell-in-cell structures and induces cancer development. The role of Ca2+ and Ca2+ channels in the process of entosis is not well understood. Here, we demonstrate that Orai1 is an entotic Ca2+ channel and provokes Ca2+ oscillations, which play a role in the engulfment of entotic cells. Furthermore, we show that SEPTIN-Orai1-Ca2+/CaM-MLCK-actomyosin axis is a mechanism by which Orai1 regulates entosis, potentially leading to cancer development.