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
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DOI：
10.1096/fj.202002031rr
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发表时间：
2022-01-01
期刊：
影响因子：
4.8
通讯作者：
Monteith, Gregory R.
中科院分区：
文献类型：
--
作者：
Bassett, John J.;Robitaille, Melanie;Monteith, Gregory R.
胞质游离Ca 2+的过度快速增加与癌细胞死亡的诱导有明确的关联。然而，表征在数小时或数天的时间内凋亡级联进展期间发生的Ca 2+信号传导事件尚不可能。现在，使用基因编码的Ca 2+指示剂，辅以自动荧光显微镜，我们已经表明，星形孢菌素诱导的MDA-MB-231乳腺癌细胞凋亡与细胞质游离Ca 2+波动的延迟发展有关，然后维持24小时。这些胞质游离Ca 2+的波动依赖于Ca 2+通道ORAI 1。在该模型中，沉默ORAI 1而不是其典型激活剂STIM 1和STIM 2促进了细胞凋亡。这种调节的途径涉及先前与癌细胞迁移相关的机制，涉及ORAI 1、伴侣蛋白SigmaR 1和Ca 2+激活的K+通道。
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.