Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 26 October 2021 / Approved: 27 October 2021 / Online: 27 October 2021 (11:16:03 CEST)

How to cite: Arora, S.; Tanwar, J.; Sharma, N.; Saurav, S.; Motiani, R.K. Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel. Preprints 2021, 2021100400 (doi: 10.20944/preprints202110.0400.v1). Arora, S.; Tanwar, J.; Sharma, N.; Saurav, S.; Motiani, R.K. Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel. Preprints 2021, 2021100400 (doi: 10.20944/preprints202110.0400.v1).

Abstract

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.

Keywords

Orai3; Store Operated Calcium entry; Pancreatic Cancer; Metastasis

Subject

LIFE SCIENCES, Other

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