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NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

Cantonero, Carlos, Camello, Pedro Javier, Abate, Carmen, Berardi, Francesco, Salido, Gines Maria, Rosado, Juan Antonio, Redondo, Pedro C.·2020·Cancers

Abstract

(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/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 σ2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other σ2R/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 σ2R/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 σ2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: σ2R/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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Metadata

Authors
Cantonero, C., Camello, P. J., Abate, C., Berardi, F., Salido, G. M., Rosado, J. A., & Redondo, P. C.
Affiliations
  • Department of Physiology, Phycell and FIMUL Groups, University of Extremadura, 10003 Caceres, Spain
  • Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via Orabona 4, I-70125 Bari, Italy
  • Institute of Molecular Pathology Biomarkers (IMPB) of University of Extremadura, 10003 Caceres, Spain
Venue
Cancers
Publisher
MDPI AG
Published
2020-01-21
Volume
12
Issue
2
Pages
257
ISSN
2072-6694
Cited by
38
References
3
Language
en

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