Role of anoctamins in cancer and apoptosis

Abstract

Anoctamin 1 (TMEM16A, Ano1) is a recently identified Ca 2+ -activated chloride channel and a member of a large protein family comprising 10 paralogues. Before Ano1 was identified as a chloride channel protein, it was known as the cancer marker DOG1. DOG1/Ano1 is expressed in gastrointestinal stromal tumours (GIST) and particularly in head and neck squamous cell carcinoma, at very high levels never detected in other tissues. It is now emerging that Ano1 is part of the 11q13 locus, amplified in several types of tumour, where it is thought to augment cell proliferation, cell migration and metastasis. Notably, Ano1 is upregulated through histone deacetylase (HDAC), corresponding to the known role of HDAC in HNSCC. As Ano1 does not enhance proliferation in every cell type, its function is perhaps modulated by cell-specific factors, or by the abundance of other anoctamins. Thus Ano6, by regulating Ca 2+ -induced membrane phospholipid scrambling and annexin V binding, supports cellular apoptosis rather than proliferation. Current findings implicate other cellular functions of anoctamins, apart from their role as Ca 2+ -activated Cl − channels.

Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

“…A pro-proliferative role of ANO1 is found in most cancer cells investigated 118,[141][142][143][144][145][146] and Stanich and coworkers demonstrated that ANO1 regulates cell proliferation at the G1/S transition in the cell cycle. 147 Other studies, however, show that cell proliferation in certain cell types is unaffected by ANO1, e.g.…”

“…140 ANO6 has received more attention in relation to apoptosis compared to ANO1 and in particular its role as a putative scramblase involved in the redistribution of phospholipids between the outer/inner membrane during apoptosis. 118,152,153 siRNA K D of ANO6 reduces cisplatin induced Caspase 3 activation (apoptosis) in ELA cells (Fig. 15) and staurosporine induced cell death in lung epithelial cells (A549 151 ).…”

“…113,114 For characterization of Anoctamin structure and function see refs. [115][116][117][118] . In the following we focus on ANO1.…”

“…[132][133][134] The coding sequence for ANO1 is located on amplicon 11q13, which contains the coding sequence for several proteins related to cell cycle, proliferation and apoptosis, and which is often amplified in cancers with poor prognosis. 118,[135][136][137][138] ANO1 is upregulated in several cancer tissues including head and neck squamous cell carcinoma, prostate, breast, pancreatic cancer and gastrointestinal stromal tumor cells. 120,[139][140][141][142] Figure 14A and 14B show overexpression of ANO1 at the mRNA level and the protein level, respectively, in PDAC cells compared to normal human pancreatic ductal epithelium cells (HPDE).…”

Ion channels in cancer: future perspectives and clinical potential

“…Cl 2 channels important for cell proliferation, cell migration and metastasis further include anoctamin 1 (TMEM16A, Ano1), which is activated by the increase in cytosolic Ca 2þ activity [127]. Ano1 expression is excessive in several gastrointestinal stromal tumours [127].…”