Kunzelmann Karl, Ousingsawat Jiraporn, Benedetto Roberta, Cabrita Ines, Schreiber Rainer
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
Cancers (Basel). 2019 Mar 19;11(3):382. doi: 10.3390/cancers11030382.
Before anoctamins (TMEM16 proteins) were identified as a family of Ca-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca levels near the plasma membrane, and/or by controlling the intracellular Cl concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis.
在anoctamins（TMEM16蛋白）被鉴定为一类钙激活氯离子通道和磷脂翻转酶之前，该家族的创始成员anoctamin 1（ANO1，TMEM16A）被称为DOG1，即胃肠道间质瘤（GIST）的一种标志物蛋白。与此同时，ANO1已得到更深入的研究，目前ANO1在细胞增殖和不同类型恶性肿瘤发展中的作用已得到充分证实。虽然ANO5、ANO7和ANO9可能也与癌症生长相关，但已有证据表明ANO6（TMEM16F）在调控细胞死亡中发挥作用。anoctamins分别控制细胞增殖和细胞死亡的细胞机制才刚刚开始显现；然而，anoctamins对细胞内钙水平的显著影响可能起着重要作用。最近的研究结果表明，一些anoctamins通过设定质膜附近的钙水平和/或控制细胞内氯离子浓度来控制膜泡外排。ANO1和ANO6诱导的胞吐作用及膜转运增加可能会增强其他氯离子通道的膜表达，如囊性纤维化跨膜传导调节因子（CFTR）和容积激活氯离子通道（VRAC）。值得注意的是，ANO6诱导的磷脂翻转及磷脂酰丝氨酸暴露对于解整合素和金属蛋白酶（ADAM）的脱落酶功能至关重要。这可能通过诱导IL-6反式信号传导来支持细胞死亡和IL-6的致瘤活性。除了通过Let-7d/CDC34轴诱导细胞周期停滞外，驱虫药氯硝柳胺所报道的抗癌作用可能与其对ANO1的强效抑制作用有关。相反，由于细胞内钙大量增加、磷脂酶A2激活或脂质过氧化导致的ANO6显著激活，可导致癌细胞发生铁死亡。因此，寻找TMEM16的抑制剂和强效激活剂以干扰癌症生长和转移似乎是合理的。
