Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells
Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca<sup>2+</sup> entry (SOCE), a major mechanism for Ca<sup>2+</sup> entry in non-excitable cells, is...
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/1/114 |
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| author | Jose Sanchez-Collado Jose J. Lopez Carlos Cantonero Isaac Jardin Sergio Regodón Pedro C. Redondo Juan Gordillo Tarik Smani Gines M. Salido Juan A. Rosado |
| author_facet | Jose Sanchez-Collado Jose J. Lopez Carlos Cantonero Isaac Jardin Sergio Regodón Pedro C. Redondo Juan Gordillo Tarik Smani Gines M. Salido Juan A. Rosado |
| author_sort | Jose Sanchez-Collado |
| collection | DOAJ |
| description | Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca<sup>2+</sup> entry (SOCE), a major mechanism for Ca<sup>2+</sup> entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca<sup>2+</sup> release-activated Ca<sup>2+</sup>) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca<sup>2+</sup> responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca<sup>2+</sup> oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca<sup>2+</sup> signals, cell proliferation and apoptosis resistance. |
| first_indexed | 2024-03-10T03:47:26Z |
| format | Article |
| id | doaj.art-85fa4035ff7e43b49f9d84694f1e81f5 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:47:26Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-85fa4035ff7e43b49f9d84694f1e81f52023-11-23T11:16:16ZengMDPI AGCancers2072-66942021-12-0114111410.3390/cancers14010114Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer CellsJose Sanchez-Collado0Jose J. Lopez1Carlos Cantonero2Isaac Jardin3Sergio Regodón4Pedro C. Redondo5Juan Gordillo6Tarik Smani7Gines M. Salido8Juan A. Rosado9Cellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainPathology Service, Hospital de Merida, 06800 Merida, SpainDepartment of Medical Physiology and Biophysics, University of Seville, 41004 Seville, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainCellular Physiology Research Group, Department of Physiology, Institute of Molecular Pathology Biomarkers (IMPB), University of Extremadura, 10003 Caceres, SpainBreast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca<sup>2+</sup> entry (SOCE), a major mechanism for Ca<sup>2+</sup> entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca<sup>2+</sup> release-activated Ca<sup>2+</sup>) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca<sup>2+</sup> responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca<sup>2+</sup> oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca<sup>2+</sup> signals, cell proliferation and apoptosis resistance.https://www.mdpi.com/2072-6694/14/1/114Orai2breast cancerstore-operated calcium entryNFATcell cycle |
| spellingShingle | Jose Sanchez-Collado Jose J. Lopez Carlos Cantonero Isaac Jardin Sergio Regodón Pedro C. Redondo Juan Gordillo Tarik Smani Gines M. Salido Juan A. Rosado Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells Cancers Orai2 breast cancer store-operated calcium entry NFAT cell cycle |
| title | Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells |
| title_full | Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells |
| title_fullStr | Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells |
| title_full_unstemmed | Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells |
| title_short | Orai2 Modulates Store-Operated Ca<sup>2+</sup> Entry and Cell Cycle Progression in Breast Cancer Cells |
| title_sort | orai2 modulates store operated ca sup 2 sup entry and cell cycle progression in breast cancer cells |
| topic | Orai2 breast cancer store-operated calcium entry NFAT cell cycle |
| url | https://www.mdpi.com/2072-6694/14/1/114 |
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