Orai1 is critical for Notch-driven aggressiveness under hypoxic conditions in triple-negative breast cancers

Orai1 is critical for Notch-driven aggressiveness under hypoxic conditions in triple-negative... It is believed that hypoxia stimulates triple-negative breast cancers (TNBCs) metastasis, which is associated with a poor prognosis. However, the underlying mechanism remains unclear. Here, we demonstrated that hypoxia up-regulates both the levels of Orai1 and Notch1, and the increase in Orai1 is mediated by Notch1 signaling in TNBCs. Functionally, Orai1 caused a sustained elevation of intracellular Ca2+ via Store-operated Ca2+ entry (SOCE), then activated the calcineurin-nuclear factor of activated T-cell 4 (NFAT4, also named NFATc3) in hypoxic TNBCs. Furthermore, pharmacologic inhibition or gene-silencing studies showed that the aggressiveness mediated by Orai1 during hypoxia is dependent on the Notch1/Orai1/SOCE/NFAT4 signaling. Moreover, Orai1 signaling also mediated hypoxia-induced angiogenesis in TNBCs. Thus, our results revealed a novel role of Orai1 as an inducer of aggression and angiogenesis under hypoxic conditions, and this suggests a novel mechanism of hypoxia-induced invasion. It may be worthwhile to further explore the potential of using Orai1 signaling as new target for anti-tumor therapy in TNBCs. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Elsevier

Orai1 is critical for Notch-driven aggressiveness under hypoxic conditions in triple-negative breast cancers

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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier B.V.
ISSN
0925-4439
D.O.I.
10.1016/j.bbadis.2018.01.003
Publisher site
See Article on Publisher Site

Abstract

It is believed that hypoxia stimulates triple-negative breast cancers (TNBCs) metastasis, which is associated with a poor prognosis. However, the underlying mechanism remains unclear. Here, we demonstrated that hypoxia up-regulates both the levels of Orai1 and Notch1, and the increase in Orai1 is mediated by Notch1 signaling in TNBCs. Functionally, Orai1 caused a sustained elevation of intracellular Ca2+ via Store-operated Ca2+ entry (SOCE), then activated the calcineurin-nuclear factor of activated T-cell 4 (NFAT4, also named NFATc3) in hypoxic TNBCs. Furthermore, pharmacologic inhibition or gene-silencing studies showed that the aggressiveness mediated by Orai1 during hypoxia is dependent on the Notch1/Orai1/SOCE/NFAT4 signaling. Moreover, Orai1 signaling also mediated hypoxia-induced angiogenesis in TNBCs. Thus, our results revealed a novel role of Orai1 as an inducer of aggression and angiogenesis under hypoxic conditions, and this suggests a novel mechanism of hypoxia-induced invasion. It may be worthwhile to further explore the potential of using Orai1 signaling as new target for anti-tumor therapy in TNBCs.

Journal

Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseElsevier

Published: Apr 1, 2018

References

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