Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel
Store operated Ca<sup>2+</sup> entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca<sup>2+</sup> influx pathway. Although the role of Orai1 channels is well studied, the significance of Orai2/3 channels is still emerging in nature. In this study...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/23/5937 |
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| author | Samriddhi Arora Jyoti Tanwar Nutan Sharma Suman Saurav Rajender K. Motiani |
| author_facet | Samriddhi Arora Jyoti Tanwar Nutan Sharma Suman Saurav Rajender K. Motiani |
| author_sort | Samriddhi Arora |
| collection | DOAJ |
| description | Store operated Ca<sup>2+</sup> entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca<sup>2+</sup> influx pathway. Although the role of Orai1 channels is well studied, the significance of Orai2/3 channels is still emerging in nature. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca<sup>2+</sup> imaging experiments in six PC cell lines and found that Orai3 forms a functional SOCE channel in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G<sub>1</sub> phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first-time reports that Orai3 drives aggressive phenotypes of PC cells, i.e., migration in vitro and metastasis in vivo. Considering that Orai3 overexpression leads to poor prognosis in PC patients, it appears to be a highly attractive therapeutic target. |
| first_indexed | 2024-03-10T04:56:43Z |
| format | Article |
| id | doaj.art-ebebe1b146654df9bf966eb3258046fd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:56:43Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ebebe1b146654df9bf966eb3258046fd2023-11-23T02:11:48ZengMDPI AGCancers2072-66942021-11-011323593710.3390/cancers13235937Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry ChannelSamriddhi Arora0Jyoti Tanwar1Nutan Sharma2Suman Saurav3Rajender K. Motiani4Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad 121001, IndiaCSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi 110025, IndiaLaboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad 121001, IndiaLaboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad 121001, IndiaLaboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad 121001, IndiaStore operated Ca<sup>2+</sup> entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca<sup>2+</sup> influx pathway. Although the role of Orai1 channels is well studied, the significance of Orai2/3 channels is still emerging in nature. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca<sup>2+</sup> imaging experiments in six PC cell lines and found that Orai3 forms a functional SOCE channel in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G<sub>1</sub> phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first-time reports that Orai3 drives aggressive phenotypes of PC cells, i.e., migration in vitro and metastasis in vivo. Considering that Orai3 overexpression leads to poor prognosis in PC patients, it appears to be a highly attractive therapeutic target.https://www.mdpi.com/2072-6694/13/23/5937Orai3store operated calcium entrypancreatic cancermetastasis |
| spellingShingle | Samriddhi Arora Jyoti Tanwar Nutan Sharma Suman Saurav Rajender K. Motiani Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel Cancers Orai3 store operated calcium entry pancreatic cancer metastasis |
| title | Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel |
| title_full | Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel |
| title_fullStr | Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel |
| title_full_unstemmed | Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel |
| title_short | Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel |
| title_sort | orai3 regulates pancreatic cancer metastasis by encoding a functional store operated calcium entry channel |
| topic | Orai3 store operated calcium entry pancreatic cancer metastasis |
| url | https://www.mdpi.com/2072-6694/13/23/5937 |
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