Store-operated Ca2+ entry as a key oncogenic Ca2+ signaling driving tumor invasion-metastasis cascade and its translational potential

Wei, Jiazhang; Deng, Yayan; Ye, Jiaxiang; Luo, Yue; Weng, Jingjin; He, Qian; Liu, Fei; Li, Min; Liang, Rong; Lin, Yan; Li, Yongqiang; Zhang, Jinyan; Yang, Jianrong; Qu, Shenhong

doi:10.1016/j.canlet.2021.05.036

Cited by 15 publications

(11 citation statements)

References 111 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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“…The details of structural insights, molecular characterization, physiological functions, pathological defects of STIM and Orai proteins, as well as their dynamic protein-protein interactions that mediated the mediate the activation of SOCE, have been extensively investigated and comprehensively reviewed [ 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 ]. Increasing evidence demonstrating the essential roles of STIM and Orai proteins have made them potential prognostic biomarkers or antitumor therapeutic targets [ 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. Here we updated the recent advances on the importance of STIM/Orai-dependent SOCE in cervical epithelial carcinogenesis and tumor malignant behaviors and the emerging development of SOCE mechanisms as the selective therapeutic target in cervical cancer.…”

Section: Intracellular Ca 2+ Homeostasis and Store-operated Ca 2+ Entry (Soce)mentioning

confidence: 99%

The Important Role of Ion Transport System in Cervical Cancer

Chen

Shen

2021

IJMS

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Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl− channels and K+-Cl− cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca2+ homeostasis, the Ca2+ store sensor STIM molecules and plasma membrane Ca2+ channel Orai proteins, the predominant Ca2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.

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Store-operated Ca2+ entry as a key oncogenic Ca2+ signaling driving tumor invasion-metastasis cascade and its translational potential

Cited by 15 publications

References 111 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

The Important Role of Ion Transport System in Cervical Cancer

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