Role of Orai3 in the Pathophysiology of Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Nov 13

PMID 34768857

Citations 9

Authors

Jose Sanchez-Collado

Isaac Jardin

Jose J Lopez

Victor Ronco

Gines M Salido

Charlotte Dubois

Natalia Prevarskaya

Juan A Rosado

Affiliations

Soon will be listed here.

Abstract

The mammalian exclusive Orai3 channel participates in the generation and/or modulation of two independent Ca currents, the store-operated current, I, involving functional interactions between the stromal interaction molecules (STIM), STIM1/STIM2, and Orai1/Orai2/Orai3, as well as the store-independent arachidonic acid (AA) (or leukotriene C4)-regulated current I, which involves Orai1, Orai3 and STIM1. Overexpression of functional Orai3 has been described in different neoplastic cells and cancer tissue samples as compared to non-tumor cells or normal adjacent tissue. In these cells, Orai3 exhibits a cell-specific relevance in Ca influx. In estrogen receptor-positive breast cancer cells and non-small cell lung cancer (NSCLC) cells store-operated Ca entry (SOCE) is strongly dependent on Orai3 expression while in colorectal cancer and pancreatic adenocarcinoma cells Orai3 predominantly modulates SOCE. On the other hand, in prostate cancer cells Orai3 expression has been associated with the formation of Orai1/Orai3 heteromeric channels regulated by AA and reduction in SOCE, thus leading to enhanced proliferation. Orai3 overexpression is associated with supporting several cancer hallmarks, including cell cycle progression, proliferation, migration, and apoptosis resistance. This review summarizes the current knowledge concerning the functional role of Orai3 in the pathogenesis of cancer.

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References

Cai X . Molecular evolution and structural analysis of the Ca(2+) release-activated Ca(2+) channel subunit, Orai. J Mol Biol. 2007; 368(5):1284-91. DOI: 10.1016/j.jmb.2007.03.022. View

Zhang X, Xin P, Yoast R, Emrich S, Johnson M, Pathak T . Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. Cell Calcium. 2020; 91:102281. PMC: 7654283. DOI: 10.1016/j.ceca.2020.102281. View

DeHaven W, Smyth J, Boyles R, Putney Jr J . Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J Biol Chem. 2007; 282(24):17548-56. DOI: 10.1074/jbc.M611374200. View

Benzerdjeb N, Sevestre H, Ahidouch A, Ouadid-Ahidouch H . Orai3 is a predictive marker of metastasis and survival in resectable lung adenocarcinoma. Oncotarget. 2016; 7(49):81588-81597. PMC: 5348414. DOI: 10.18632/oncotarget.13149. View

Yang P, Cartwright C, Li J, Wen S, Prokhorova I, Shureiqi I . Arachidonic acid metabolism in human prostate cancer. Int J Oncol. 2012; 41(4):1495-503. PMC: 3982713. DOI: 10.3892/ijo.2012.1588. View

Motiani R, Abdullaev I, Trebak M . A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells. J Biol Chem. 2010; 285(25):19173-83. PMC: 2885196. DOI: 10.1074/jbc.M110.102582. View

Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A . CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr Biol. 2007; 17(9):794-800. PMC: 5663639. DOI: 10.1016/j.cub.2007.03.065. View

Lee K, Yuan J, Zeng W, So I, Worley P, Muallem S . Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels. Proc Natl Acad Sci U S A. 2009; 106(34):14687-92. PMC: 2732841. DOI: 10.1073/pnas.0904664106. View

Magnon C, Hall S, Lin J, Xue X, Gerber L, Freedland S . Autonomic nerve development contributes to prostate cancer progression. Science. 2013; 341(6142):1236361. DOI: 10.1126/science.1236361. View

10.

Xu S, Zeng F, Boulay G, Grimm C, Harteneck C, Beech D . Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol. 2005; 145(4):405-14. PMC: 1576154. DOI: 10.1038/sj.bjp.0706197. View

11.

Singh A, Roy N, Bordoloi D, Padmavathi G, Banik K, Khwairakpam A . Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-κB signalling. Life Sci. 2020; 261:118372. DOI: 10.1016/j.lfs.2020.118372. View

12.

Frischauf I, Schindl R, Bergsmann J, Derler I, Fahrner M, Muik M . Cooperativeness of Orai cytosolic domains tunes subtype-specific gating. J Biol Chem. 2011; 286(10):8577-8584. PMC: 3048740. DOI: 10.1074/jbc.M110.187179. View

13.

Mignen O, Thompson J, Shuttleworth T . The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. J Physiol. 2009; 587(Pt 17):4181-97. PMC: 2754359. DOI: 10.1113/jphysiol.2009.174193. View

14.

Zhu D, He R, Yu W, Li C, Cheng H, Zhu B . ORAI3 contributes to hypoxia-inducible factor 1/2α-sensitive colon cell migration. Physiol Int. 2021; . DOI: 10.1556/2060.2021.00137. View

15.

Jardin I, Diez-Bello R, Falcon D, Alvarado S, Regodon S, Salido G . Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells. J Biol Chem. 2020; 296:100254. PMC: 7948746. DOI: 10.1074/jbc.RA120.015769. View

16.

Thompson J, Mignen O, Shuttleworth T . The N-terminal domain of Orai3 determines selectivity for activation of the store-independent ARC channel by arachidonic acid. Channels (Austin). 2010; 4(5):398-410. PMC: 3037817. DOI: 10.4161/chan.4.5.13226. View

17.

Takahashi Y, Murakami M, Watanabe H, Hasegawa H, Ohba T, Munehisa Y . Essential role of the N-terminus of murine Orai1 in store-operated Ca2+ entry. Biochem Biophys Res Commun. 2007; 356(1):45-52. DOI: 10.1016/j.bbrc.2007.02.107. View

18.

Azimi I, Milevskiy M, Chalmers S, Yapa K, Robitaille M, Henry C . ORAI1 and ORAI3 in Breast Cancer Molecular Subtypes and the Identification of ORAI3 as a Hypoxia Sensitive Gene and a Regulator of Hypoxia Responses. Cancers (Basel). 2019; 11(2). PMC: 6406924. DOI: 10.3390/cancers11020208. View

19.

Sanchez-Collado J, Lopez J, Gonzalez-Gutierrez L, Cantonero C, Jardin I, Salido G . Functional role of TRPC6 and STIM2 in cytosolic and endoplasmic reticulum Ca2+ content in resting estrogen receptor-positive breast cancer cells. Biochem J. 2020; 477(17):3183-3197. DOI: 10.1042/BCJ20200560. View

20.

Schindl R, Frischauf I, Bergsmann J, Muik M, Derler I, Lackner B . Plasticity in Ca2+ selectivity of Orai1/Orai3 heteromeric channel. Proc Natl Acad Sci U S A. 2009; 106(46):19623-8. PMC: 2780800. DOI: 10.1073/pnas.0907714106. View