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ORAI1 regulates sustained cytosolic free calcium fluctuations during breast cancer cell apoptosis and apoptotic resistance via a STIM1 independent pathway

ORAI1 regulates sustained cytosolic free calcium fluctuations during breast cancer cell apoptosis and apoptotic resistance via a STIM1 independent pathway

By John J Bassett , Mélanie Robitaille, Amelia A Peters, Alice H L Bong , Meng-Wong Taing, Ian A Wood, Francisco Sadras, Sarah J Roberts-Thomson, and Gregory R Monteith

Introduction to the article published in FASEB J. 2022 Jan;36(1):e22108. DOI: 10.1096/fj.202002031RR PMID: 34939697.

Editor’s Highlights

  • The chaperone protein SigmaRl, the small conductance Ca2+-activated IC+ channels SK2 (KCNN2) and SK3 (KCNN3) and ORAI1. SigmaR1 silencing, like ORAI1 silencing, promoted STS-induced apoptosis.
  • The interaction between SK2/3, SigmaR1 and ORAI1 not only regulates cancer cell migration but also pathways that provide a degree of protection against apoptosis.
  • SigmaR1 silencing contributes to the increased induction of apoptosis.
  • Co-expression of spectrally distinct GECIs measuring mitochondrial Ca2+ and [Ca2+]cYT with SigmaR1 and ORAI1 silencing could address this hypothesis.
  • The role of ORAI1 in apoptosis is mechanistically linked to a non-SOCE dependent pathway, involving SigmaR1 and SK2/ 3 K± channels.
  • Sigma-1 receptor antagonist will contribute to cancer cell apoptosis

See also: Orai1/KCa/SigmaR1 complex, the cancer cell suicide squad, by Mathieu Gautier and Christophe Vandier, Cell Calcium, Volume 104, 2022, 102568,ISSN 0143-4160, DO: https://doi.org/10.1016/j.ceca.2022.102568.

Abstract

Excessive rapid increases in cytosolic free Ca2+ have a clear association with the induction of cancer cell death. Whereas, characterizing the Ca2+ signaling events that occur during the progression of the apoptotic cascade over a period of hours or days, has not yet been possible. Now using genetically encoded Ca2+ indicators complemented with automated epifluorescence microscopy we have shown that staurosporine-induced apoptosis in MDA-MB-231 breast cancer cells was associated with delayed development of cytosolic free Ca2+ fluctuations, which were then maintained for 24 h. These cytosolic free Ca2+ fluctuations were dependent on the Ca2+ channel ORAI1. Silencing of ORAI1, but not its canonical activators STIM1 and STIM2, promoted apoptosis in this model. The pathway for this regulation implicates a mechanism previously associated with the migration of cancer cells involving ORAI1, the chaperone protein SigmaR1, and Ca2+ -activated K+channels.