Journal
CANCERS
Volume 12, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/cancers12020257
Keywords
sigma 2R/TMEM97; STIM1; SOCE; NO1; MDA-MB-231 cells
Categories
Funding
- MINECO [BFU2013-45564C2-1-P, BFU2016-74932-C2-1-P]
- Junta de Extremadura-FEDER [GR18061, IB16046]
- Junta de Extremadura [PD16072]
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(1) Background: The structure of the Sigma 2 receptor/TMEM97 (sigma 2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of sigma 2R/TMEM97. The novel sigma 2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis. Greater bioaccumulation and faster uptake of NO1 in MDA-MB-231 cells compared to MCF10A or MCF7 cell lines were also shown. Accordingly, elevated sigma 2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other sigma 2R/TMEM97 ligands, such as SM21 and PB28, enhanced MDA-MB-231 cell proliferation and migration. Store-operated calcium entry (SOCE) is crucial for different cancer hallmarks. Here, we show that NO1, but not other sigma 2R/TMEM97 ligands, reduced SOCE in MDA-MB-231 cells. Similarly, TMEM97 silencing in MDA-MB-231 cells also impaired SOCE. NO1 administration downregulated STIM1-Orai1 interaction, probably by impairing the positive regulatory effect of sigma 2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: sigma 2R/TMEM97 is a key protein for the survival of triple negative breast cancer cells by promoting SOCE; therefore, NO1 may become a good pharmacological tool to avoid their proliferation.
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