Store Operated Calcium Entry in Cell Migration and Cancer Metastasis

Hammad, Ayat S.; Machaca, Khaled

doi:10.3390/cells10051246

Cited by 40 publications

(35 citation statements)

References 142 publications

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“…We next performed studies for identifying potential mechanisms functioning downstream of Orai3 for regulating PC metastasis. Since metastasis is a very complex phenomenon involving several steps, based on the literature survey suggesting a role for SOCE in regulating MMP expression and EMT [ 42 , 43 , 44 , 45 ], we only focused on MMP expression and EMT in this study. Recently, STIM1-Orai1 mediated SOCE was shown to regulate expression of key metastasis associated MMP2 expression [ 43 ] in cancerous cells.…”

Section: Resultsmentioning

confidence: 99%

“…Collectively, our in vivo studies suggest that Orai3 regulates PC metastasis ( Figure 9 ). Indeed, the role of Orai channels mediated SOCE in driving cancer cell migration and metastasis is starting to emerge in a variety of cancer types [ 44 , 45 , 50 ]. However, molecular mechanisms driving metastasis downstream of SOCE remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Arora

Tanwar

Sharma

et al. 2021

Cancers

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Arora

Tanwar

Sharma

et al. 2021

Cancers

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show abstract

“…Interestingly, our in vivo studies suggest that Orai3 regulates PC metastasis (Figure 9). Indeed, the role of Orai channels mediated SOCE in driving cancer cell migration and metastasis is starting to emerge in a variety of cancer types [44,45,50]. However, molecular mechanisms driving metastasis downstream of SOCE remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…We next performed studies for identifying potential mechanisms functioning downstream of Orai3 for regulating PC metastasis. Since metastasis is very complex phenomenon involving several steps, based on literature survey suggesting role of SOCE in regulating MMP expression and EMT [42][43][44][45], we only focused on MMP expression and EMT in this study. Recently, STIM1-Orai1 mediated SOCE was shown to regulate expression of key metastasis associated MMP2 expression [43] in cancerous cells.…”

Section: Orai3 Regulates Pc Progression and Metastasis In Vivomentioning

confidence: 99%

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Arora¹,

Tanwar²,

Sharma³

et al. 2021

Preprint

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Pancreatic 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. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. 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 6 PC cell lines and found that Orai3 forms a functional SOCE 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 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

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“…Among all the actors involved in cell migration, calcium (Ca 2+ ) plays a pivotal role [ 13 ]. Numerous studies have demonstrated the role of Ca 2+ influx in regulating the migration of cancer cells and more specifically breast cancer cells [ 14 , 15 , 16 ]. Orai channels, whose activity is linked to the filling state of intracellular Ca 2+ stores, are among the major players in mediating the entry of Ca 2+ into non-excitable cells [ 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Orai3 Calcium Channel Regulates Breast Cancer Cell Migration through Calcium-Dependent and -Independent Mechanisms

Chamlali

Kouba

Rodat-Despoix

et al. 2021

Cells

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Orai3 calcium (Ca2+) channels are implicated in multiple breast cancer processes, such as proliferation and survival as well as resistance to chemotherapy. However, their involvement in the breast cancer cell migration processes remains vague. In the present study, we exploited MDA-MB-231 and MDA-MB-231 BrM2 basal-like estrogen receptor-negative (ER−) cell lines to assess the direct role of Orai3 in cell migration. We showed that Orai3 regulates MDA-MB-231 and MDA-MB-231 BrM2 cell migration in two distinct ways. First, we showed that Orai3 remodels cell adhesive capacities by modulating the intracellular Ca2+ concentration. Orai3 silencing (siOrai3) decreased calpain activity, cell adhesion and migration in a Ca2+-dependent manner. In addition, Orai3 interacts with focal adhesion kinase (FAK) and regulates the actin cytoskeleton, in a Ca2+-independent way. Thus, siOrai3 modulates cell morphology by altering F-actin polymerization via a loss of interaction between Orai3 and FAK. To summarize, we demonstrated that Orai3 regulates cell migration through a Ca2+-dependent modulation of calpain activity and, in a Ca2+-independent manner, the actin cytoskeleton architecture via FAK.

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Store Operated Calcium Entry in Cell Migration and Cancer Metastasis

Cited by 40 publications

References 142 publications

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Orai3 Calcium Channel Regulates Breast Cancer Cell Migration through Calcium-Dependent and -Independent Mechanisms

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