Contribution of Anoctamins to Cell Survival and Cell Death

Abstract

Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-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 Ca2+ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca2+i 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.

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

“…2e, f). The results demonstrate an essential role of TMEM16A for proliferation of cysts, electrolyte secretion into the cysts, or both 8,18 (Fig. 2e, f).…”

Niclosamide repurposed for the treatment of inflammatory airway disease

“…This paper discusses the importance of TMEM16A/F for mucus production and secretion and identifies TMEM16A/F as targets of the anthelmintic drug niclosamide (21). Nevertheless, it is entirely possible that niclosamide acts via additional mechanisms, which are independent of TMEM16A/F (37,38). We recently provided evidence that TMEM16A and TMEM16F can replace each other in exerting their proexocytic effects (25).…”

TMEM16A drives renal cyst growth by augmenting Ca2+ signaling in M1 cells

“…Remarkably, primary cilia present in terminally differentiated naïve cells or in non-proliferating cells in culture, contain TMEM16A as well as the paralogous proteins TMEM16F and TMEM16K [8][9][10]. Loss of expression of TMEM16A was shown to compromise ciliary genesis and decreased length of the primary cilium and of motile cilia [8,11,12].…”