Academic Journal
Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells
| Title: | Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells |
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| Authors: | Duan Zhuo, Zhenchuan Lei, Lin Dong, Andrew Man Lok Chan, Jiacheng Lin, Liwen Jiang, Beibei Qiu, Xiaohua Jiang, Youhua Tan, Xiaoqiang Yao |
| Source: | Stem Cell Research & Therapy, Vol 15, Iss 1, Pp 1-16 (2024) |
| Publisher Information: | BMC, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Medicine (General) LCC:Biochemistry |
| Subject Terms: | Breast cancer stem cells, Orai1, Orai3, Glycolysis, Medicine (General), R5-920, Biochemistry, QD415-436 |
| More Details: | Abstract Background One of major challenges in breast tumor therapy is the existence of breast cancer stem cells (BCSCs). BCSCs are a small subpopulation of tumor cells that exhibit characteristics of stem cells. BCSCs are responsible for progression, recurrence, chemoresistance and metastasis of breast cancer. Ca2+ signalling plays an important role in diverse processes in cancer development. However, the role of Ca2+ signalling in BCSCs is still poorly understood. Methods A highly effective 3D soft fibrin gel system was used to enrich BCSC-like cells from ER+ breast cancer lines MCF7 and MDA-MB-415. We then investigated the role of two Ca2+-permeable ion channels Orai1 and Orai3 in the growth and stemness of BCSC-like cells in vitro, and tumorigenicity in female NOD/SCID mice in vivo. Results Orai1 RNA silencing and pharmacological inhibition reduced the growth of BCSC-like cells in tumor spheroids, decreased the expression levels of BCSC markers, and reduced the growth of tumor xenografts in NOD/SCID mice. Orai3 RNA silencing also had similar inhibitory effect on the growth and stemness of BCSC-like cells in vitro, and tumor xenograft growth in vivo. Mechanistically, Orai1 and SPCA2 mediate store-operated Ca2+ entry. Knockdown of Orai1 or SPCA2 inhibited glycolysis pathway, whereas knockdown of Orai3 or STIM1 had no effect on glycolysis. Conclusion We found that Orai1 interacts with SPCA2 to mediate store-independent Ca2+ entry, subsequently promoting the growth and tumorigenicity of BCSC-like cells via glycolysis pathway. In contrast, Orai3 and STIM1 mediate store-operated Ca2+ entry, promoting the growth and tumorigenicity of BCSC-like cells via a glycolysis-independent pathway. Together, our study uncovered a well-orchestrated mechanism through which two Ca2+ entry pathways act through distinct signalling axes to finely control the growth and tumorigenicity of BCSCs. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1757-6512 |
| Relation: | https://doaj.org/toc/1757-6512 |
| DOI: | 10.1186/s13287-024-03875-1 |
| Access URL: | https://doaj.org/article/63d4c9c768ef4ea1a736da1c5c8a38ac |
| Accession Number: | edsdoj.63d4c9c768ef4ea1a736da1c5c8a38ac |
| Database: | Directory of Open Access Journals |
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| ISSN: | 17576512 |
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| DOI: | 10.1186/s13287-024-03875-1 |
| Published in: | Stem Cell Research & Therapy |
| Language: | English |