Abstract
Ca2+ 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 Ca2+ 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.
Highlights
TMEM16A-K form a family of 10 paralogous proteins that are Ca2+ activated phospholipid scramblases and ion channels [1,2,3]
We show that TMEM16F is activated during erastin and RSL3-induced ferroptosis
2019, 11, 625 of 15 data demonstrate a central role of TMEM16F during ferroptotic cell death, we propose 10 direct activation of TMEM16F as a promising new strategy to interfere with cancer growth
Summary
TMEM16A-K (anoctamin 1–10) form a family of 10 paralogous proteins that are Ca2+ activated phospholipid scramblases and ion channels [1,2,3]. These proteins are broadly expressed and fulfill numerous functions in epithelial cells and other non-excitable tissues, as well neurons, smooth muscles and sensory cells. The Ca2+ activated Cl− channel TMEM16A has been analyzed in great detail, and has been found along with other members of the TMEM16 family to control cell proliferation and growth of different types of cancer Gasdermin D generates large plasma membrane pores, Cancers 2019, 11, 625; doi:10.3390/cancers11050625 www.mdpi.com/journal/cancers
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