Ousingsawat Jiraporn, Schreiber Rainer, Kunzelmann Karl
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
Cancers (Basel). 2019 May 5;11(5):625. doi: 10.3390/cancers11050625.
Ca activated Cl channels (TMEM16A; ANO1) support cell proliferation and cancer growth. Expression of TMEM16A is strongly enhanced in different types of malignomas. In contrast, TMEM16F (ANO6) operates as a Ca activated chloride/nonselective ion channel and scrambles membrane phospholipids to expose phosphatidylserine at the cell surface. Both phospholipid scrambling and cell swelling induced through activation of nonselective ion currents appear to destabilize the plasma membrane thereby causing cell death. There is growing evidence that activation of TMEM16F contributes to various forms of regulated cell death. In the present study, we demonstrate that ferroptotic cell death, occurring during peroxidation of plasma membrane phospholipids activates TMEM16F. Ferroptosis was induced by erastin, an inhibitor of the cystine-glutamate antiporter and RSL3, an inhibitor of glutathione peroxidase 4 (GPX4). Cell death was largely reduced in the intestinal epithelium, and in peritoneal macrophages isolated from mice with tissue-specific knockout of TMEM16F. We show that TMEM16F is activated during erastin and RSL3-induced ferroptosis. In contrast, inhibition of ferroptosis by ferrostatin-1 and by inhibitors of TMEM16F block TMEM16F currents and inhibit cell death. We conclude that activation of TMEM16F is a crucial component during ferroptotic cell death, a finding that may be useful to induce cell death in cancer cells.
钙激活氯离子通道（TMEM16A；ANO1）支持细胞增殖和肿瘤生长。TMEM16A在不同类型的恶性肿瘤中表达显著增强。相比之下，TMEM16F（ANO6）作为一种钙激活氯离子/非选择性离子通道，可使膜磷脂紊乱，从而使磷脂酰丝氨酸暴露于细胞表面。通过激活非选择性离子电流诱导的磷脂紊乱和细胞肿胀似乎会破坏质膜的稳定性，从而导致细胞死亡。越来越多的证据表明，TMEM16F的激活与各种形式的程序性细胞死亡有关。在本研究中，我们证明了在质膜磷脂过氧化过程中发生的铁死亡性细胞死亡会激活TMEM16F。铁死亡由胱氨酸-谷氨酸反向转运体抑制剂厄洛替尼和谷胱甘肽过氧化物酶4（GPX4）抑制剂RSL3诱导。在肠道上皮以及从组织特异性敲除TMEM16F的小鼠中分离出的腹腔巨噬细胞中，细胞死亡显著减少。我们表明，在厄洛替尼和RSL3诱导的铁死亡过程中，TMEM16F被激活。相比之下，铁死亡抑制剂铁抑素-1和TMEM16F抑制剂可阻断TMEM16F电流并抑制细胞死亡。我们得出结论，TMEM16F的激活是铁死亡性细胞死亡过程中的一个关键组成部分，这一发现可能有助于诱导癌细胞死亡。
