We thank Mrs Marianne Karlsberg (CliniXion Ltd, Tampere, Finland) and Sanna Virtanen, MSc (Dermagene Oy) for performing the FISH assays, Mrs Jonna Varis for cell culturing, Mrs Kaija J?rvinen for performing the immunohistochemistry U0126 cost assays, and Mrs Marjukka Nyk?nen for constructing the tissue microarrays. Footnotes Supplementary Information accompanies the paper on British Journal of Cancer website (http://www.nature.com/bjc) This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Supplementary Material Supplementary Figures 1 and 2 Click here for additional data file.(93K, doc) Supplementary Tables 1�C4 Click here for additional data file.

(153K, doc) Supplementary online material methods 1�C4 Click here for additional data file.(35K, doc)
Calcium-activated Cl? channels (CaCCs) are widely expressed in epithelial and nonepithelial cell types, where they facilitate epithelial fluid secretion, smooth muscle contraction, neurosensory signaling, and other functions (1�C3). TMEM16A (alternative name, anoctamin-1, ANO1) was identified as a CaCC, as its heterologous expression in oocytes and mammalian cells produced outwardly rectifying, Ca2+-sensitive Cl? currents (4�C6). TMEM16A is expressed in epithelial cells in airways, salivary gland, intestine, and other tissues, as well as in arterial smooth muscle, intestinal pacemaker cells, sensory neurons, and various tumors (4, 7�C9).

Though TMEM16A-knockout mice die just after birth because of tracheomalacia (10), electrophysiological measurements in the neonatal knockout mice suggested TMEM16A involvement in chloride secretion in salivary gland (11) and airway (12) epithelia. Evidence has also been reported for TMEM16A involvement in intestinal and vascular smooth muscle contraction, nociception, and bile formation (9, 13�C15). We recently identified, by high-throughput screening, small-molecule inhibitors of TMEM16A chloride conductance. Some compounds, including tannic acid and related gallotannins (16) and the arylaminothiophene CaCCinh-A01 (17), function as nonselective CaCC inhibitors that inhibit TMEM16A and other, as yet unidentified, CaCCs in multiple cell types.

We proposed that CaCC inhibition by gallotannins in red wines and green teas may account, in part, for their health benefits, including reduced risk of cardiovascular disease. TMEM16A-selective inhibitors were also identified, including the aminophenylthiazole, T16Ainh-A01 (18). T16Ainh-A01 inhibited CaCC Cl? current in TMEM16A-transfected cells and in cultures AV-951 of human salivary gland and IL-4-treated bronchial epithelia, but not in intestine, providing pharmacological data on TMEM16A involvement in CaCC function in various tissues.