Abstract
Simple SummaryPancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Here, we demonstrate that a highly Ca2+ selective plasma membrane channel Orai3 is overexpressed in PC and is associated with poor prognosis in PC patients. Our data demonstrate that Orai3 modulates PC cell proliferation, apoptosis and migration. We further reveal that Orai3 regulates PC metastasis in immune-compromised mice. Collectively, our study establishes Orai3 as an attractive therapeutic target for managing PC metastasis, which may lead to better prognosis.Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca2+ 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 Ca2+ 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 G1 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.
Highlights
Pancreatic cancer (PC) is one of the deadliest cancers causing ~5 lakh deaths annually [1]
We evaluated the association of higher Orai3 expression to the mean survival time of the PC patients using “GEPIA” and “The Human Protein Atlas”
The “GEPIA” analysis for 89 samples with high Orai3 expression and 89 samples with relatively low Orai3 levels demonstrated that none of the PC patients with higher Orai3 expression could survive beyond 5.5 years while, ~20% PC patients with low Orai3 expression survived more than 7.5 years (Figure 1B)
Summary
Pancreatic cancer (PC) is one of the deadliest cancers causing ~5 lakh deaths annually [1]. In response to Ca2+ store depletion, STIM1/STIM2 molecules oligomerize and physically interact with plasma membrane Orai channels at ER-PM junctions. This communication leads to opening of the Orai channels and Ca2+ influx into the cells [11,12]. The Ca2+ entry by Orai channels drives vital cellular functions in a variety of cell types [13,14,15,16]. Both hypo and hyper functioning of Orai channels leads to pathological consequences [16,17]
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