Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 832, Issue -, Pages 1-10Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2018.05.008
Keywords
Colon cancer; Hypoxia; Orai1; Invasiveness; Angiogenesis
Categories
Funding
- National Natural Science Foundation of China [81622007, 81572940, 81700283, 81700437]
- Fundamental Research Funds for the Central Universities [JUSRP51704A, JUSRP11747]
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In colon cancer, hypoxia promotes metastasis and angiogenesis, but little is known about the mediators of these effects. Here, we reported that expression of Orai1 is up-regulated in colon cancer cells in response to hypoxia, and the increase in Orai1 is mediated by Notchl pathway. We also showed upregulation of Orai1 contributes to hypoxia-induced invasion and angiogenesis, and inhibition or downregulation of Orai1 reverses these effects. Mechanistic study revealed that upregulation of Orai1 by hypoxia potentiates store-operated Ca2+ entry (SOCE), and then causes activation of nuclear factor of activated T cells isoform c3 (NFATc3) in colon cancer cells. Furthermore, expression of Orai1 was correlated with tumor metastasis in patients. These results identify Orai1 as a novel target gene of hypoxia and reveal the role of Orai1 signaling in regulating hypoxia-induced invasiveness and angiogenesis under hypoxic conditions. Strategies to target this signaling might be developed to treat colon cancer metastasis and angiogenesis associated with hypoxia.
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