Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

Molecular Cancer - Tập 16 - Trang 1-17 - 2017
Hui Wang1, Liang Zou2, Ke Ma1, Jiankun Yu1, Huizhe Wu3, Minjie Wei3, Qinghuan Xiao1
1Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
2Department of Anesthesiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
3Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China

Tóm tắt

TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.

Tài liệu tham khảo

Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U. TMEM16A Confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455:1210–5. Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ. TMEM16A, A membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322:590–4. Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134:1019–29. Grubb S, Poulsen KA, Juul CA, Kyed T, Klausen TK, Larsen EH, Hoffmann EK. TMEM16F (Anoctamin 6), an anion channel of delayed ca(2+) activation. J Gen Physiol. 2013;141:585–600. Schreiber R, Uliyakina I, Kongsuphol P, Warth R, Mirza M, Martins JR, Kunzelmann K. Expression and function of epithelial anoctamins. J Biol Chem. 2010;285:7838–45. Pifferi S, Dibattista M, Menini A. TMEM16B Induces chloride currents activated by calcium in mammalian cells. Pflugers Arch. 2009;458:1023–38. Suzuki J, Fujii T, Imao T, Ishihara K, Kuba H, Nagata S. Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J Biol Chem. 2013;288:13305–16. Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature. 2010;468:834–8. Yang H, Kim A, David T, Palmer D, Jin T, Tien J, Huang F, Cheng T, Coughlin SR, Jan YN, Jan LY. TMEM16F Forms a Ca2+−activated cation channel required for lipid scrambling in platelets during blood coagulation. Cell. 2012;151:111–22. Tian Y, Schreiber R, Kunzelmann K. Anoctamins are a family of Ca2+−activated Cl- channels. J Cell Sci. 2012;125:4991–8. Whitlock JM, Hartzell HC. Anoctamins/TMEM16 proteins: chloride channels flirting with lipids and extracellular vesicles. Annu Rev Physiol. 2016; Xiao Q, Yu K, Perez-Cornejo P, Cui Y, Arreola J, Hartzell HC. Voltage- and calcium-dependent gating of TMEM16A/Ano1 chloride channels are physically coupled by the first intracellular loop. Proc Natl Acad Sci U S A. 2011;108:8891–6. Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature. 2014;516:207–12. Ma K, Wang H, Yu J, Wei M, Xiao Q. New insights on the regulation of Ca2+ −activated Chloride Channel TMEM16A. J Cell Physiol. 2017;232:707–16. Jeng G, Aggarwal M, Yu WP, Chen TY. Independent activation of distinct pores in dimeric TMEM16A channels. J Gen Physiol. 2016;148:393–404. Lim NK, Lam AK, Dutzler R. Independent activation of ion conduction pores in the double-barreled calcium-activated chloride channel TMEM16A. J Gen Physiol. 2016;148:375–92. Rock JR, O'Neal WK, Gabriel SE, Randell SH, Harfe BD, Boucher RC, Grubb BR. Transmembrane protein 16A (TMEM16A) is a Ca2+−regulated Cl- secretory channel in mouse airways. J Biol Chem. 2009;284:14875–80. Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD, Donne ML, Huang X, Sheppard D, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE, Li M, Jan YN, Jan LY, Rock JR. Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction. Proc Natl Acad Sci U S A. 2012;109:16354–9. Almaca J, Tian Y, Aldehni F, Ousingsawat J, Kongsuphol P, Rock JR, Harfe BD, Schreiber R, Kunzelmann K. TMEM16 Proteins produce volume-regulated chloride currents that are reduced in mice lacking TMEM16A. J Biol Chem. 2009;284:28571–8. Wang M, Yang H, Zheng LY, Zhang Z, Tang YB, Wang GL, Du YH, Lv XF, Liu J, Zhou JG, Guan YY. Downregulation of TMEM16A calcium-activated chloride channel contributes to cerebrovascular remodeling during hypertension by promoting basilar smooth muscle cell proliferation. Circulation. 2012;125:697–707. Manoury B, Tamuleviciute A, Tammaro P. TMEM16A/Anoctamin 1 protein mediates calcium-activated chloride currents in pulmonary arterial smooth muscle cells. J Physiol. 2010;588:2305–14. Thomas-Gatewood C, Neeb ZP, Bulley S, Adebiyi A, Bannister JP, Leo MD, Jaggar JH. TMEM16A Channels generate ca(2)(+)-activated Cl(−) currents in cerebral artery smooth muscle cells. Am J Physiol Heart Circ Physiol. 2011;301:H1819–27. Ma MM, Gao M, Guo KM, Wang M, Li XY, Zeng XL, Sun L, Lv XF, Du YH, Wang GL, Zhou JG, Guan YY. TMEM16A Contributes to endothelial dysfunction by facilitating Nox2 NADPH Oxidase-derived reactive oxygen species generation in hypertension. Hypertension. 2017; Wu MM, Lou J, Song BL, Gong YF, Li YC, Yu CJ, Wang QS, Ma TX, Ma K, Hartzell HC, Duan DD, Zhao D, Zhang ZR. Hypoxia augments the calcium-activated chloride current carried by anoctamin-1 in cardiac vascular endothelial cells of neonatal mice. Br J Pharmacol. 2014;171:3680–92. Hwang SJ, Blair PJ, Britton FC, O'Driscoll KE, Hennig G, Bayguinov YR, Rock JR, Harfe BD, Sanders KM, Ward SM. Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol. 2009;587:4887–904. Huang F, Rock JR, Harfe BD, Cheng T, Huang X, Jan YN, Jan LY. Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc Natl Acad Sci U S A. 2009;106:21413–8. Liu B, Linley JE, Du X, Zhang X, Ooi L, Zhang H, Gamper N. The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+−activated Cl- channels. J Clin Invest. 2010;120:1240–52. Takayama Y, Uta D, Furue H, Tominaga M. Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons. Proc Natl Acad Sci U S A. 2015;112:5213–8. Cho H, Yang YD, Lee J, Lee B, Kim T, Jang Y, Back SK, Na HS, Harfe BD, Wang F, Raouf R, Wood JN, Oh U. The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons. Nat Neurosci. 2012;15:1015–21. Oh U, Jung J. Cellular functions of TMEM16/anoctamin. Pflugers Arch. 2016;468:443–53. Pedemonte N, Galietta LJ. Structure and function of TMEM16 proteins (anoctamins). Physiol Rev. 2014;94:419–59. Hartzell HC, Yu K, Xiao Q, Chien LT, Qu Z. Anoctamin/TMEM16 family members are Ca2+−activated Cl- channels. J Physiol. 2009;587:2127–39. Wanitchakool P, Ousingsawat J, Sirianant L, MacAulay N, Schreiber R, Kunzelmann K. Cl- channels in apoptosis. Eur Biophys J. 2016; Mazzone A, Bernard CE, Strege PR, Beyder A, Galietta LJ, Pasricha PJ, Rae JL, Parkman HP, Linden DR, Szurszewski JH, Ordog T, Gibbons SJ, Farrugia G. Altered expression of Ano1 variants in human diabetic gastroparesis. J Biol Chem. 2011;286:13393–403. Sondo E, Caci E, Galietta LJ. The TMEM16A chloride channel as an alternative therapeutic target in cystic fibrosis. Int J Biochem Cell Biol. 2014;52:73–6. Wang B, Li C, Huai R, Qu Z. Overexpression of ANO1/TMEM16A, an arterial Ca2+−activated Cl- channel, contributes to spontaneous hypertension. J Mol Cell Cardiol. 2015;82:22–32. Huang X, Gollin SM, Raja S, Godfrey TE. High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells. Proc Natl Acad Sci U S A. 2002;99:11369–74. Carles A, Millon R, Cromer A, Ganguli G, Lemaire F, Young J, Wasylyk C, Muller D, Schultz I, Rabouel Y, Dembele D, Zhao C, Marchal P, Ducray C, Bracco L, Abecassis J, Poch O, Wasylyk B. Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display. Oncogene. 2006;25:1821–31. West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R, Goldblum JR, Brown PO, Heinrich MC, van de Rijn M. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004;165:107–13. Katoh M, Katoh M. FLJ10261 Gene, located within the CCND1-EMS1 locus on human chromosome 11q13, encodes the eight-transmembrane protein homologous to C12orf3, C11orf25 and FLJ34272 gene products. Int J Oncol. 2003;22:1375–81. Carneiro A, Isinger A, Karlsson A, Johansson J, Jonsson G, Bendahl PO, Falkenback D, Halvarsson B, Nilbert M. Prognostic impact of array-based genomic profiles in esophageal squamous cell cancer. BMC Cancer. 2008;8:98. Britschgi A, Bill A, Brinkhaus H, Rothwell C, Clay I, Duss S, Rebhan M, Raman P, Guy CT, Wetzel K, George E, Popa MO, Lilley S, Choudhury H, Gosling M, Wang L, Fitzgerald S, Borawski J, Baffoe J, Labow M, Gaither LA, Bentires-Alj M. Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling. Proc Natl Acad Sci U S A. 2013;110:E1026–34. Wu H, Guan S, Sun M, Yu Z, Zhao L, He M, Zhao H, Yao W, Wang E, Jin F, Xiao Q, Wei M. Ano1/TMEM16A Overexpression is associated with good prognosis in PR-positive or HER2-negative breast cancer patients following Tamoxifen treatment. PLoS One. 2015;10:e0126128. Duvvuri U, Shiwarski DJ, Xiao D, Bertrand C, Huang X, Edinger RS, Rock JR, Harfe BD, Henson BJ, Kunzelmann K, Schreiber R, Seethala RS, Egloff AM, Chen X, Lui VW, Grandis JR, Gollin SM. TMEM16A Induces MAPK and contributes directly to tumorigenesis and cancer progression. Cancer Res. 2012;72:3270–81. Ruiz C, Martins JR, Rudin F, Schneider S, Dietsche T, Fischer CA, Tornillo L, Terracciano LM, Schreiber R, Bubendorf L, Kunzelmann K. Enhanced expression of ANO1 in head and neck squamous cell carcinoma causes cell migration and correlates with poor prognosis. PLoS One. 2012;7:e43265. Ayoub C, Wasylyk C, Li Y, Thomas E, Marisa L, Robe A, Roux M, Abecassis J, de Reynies A, Wasylyk B. ANO1 Amplification and expression in HNSCC with a high propensity for future distant metastasis and its functions in HNSCC cell lines. Br J Cancer. 2010;103:715–26. Rodrigo JP, Menendez ST, Hermida-Prado F, Alvarez-Teijeiro S, Villaronga MA, Alonso-Duran L, Vallina A, Martinez-Camblor P, Astudillo A, Suarez C, Maria G-PJ. Clinical significance of Anoctamin-1 gene at 11q13 in the development and progression of head and neck squamous cell carcinomas. Sci Rep. 2015;5:15698. Sui Y, Sun M, Wu F, Yang L, Di W, Zhang G, Zhong L, Ma Z, Zheng J, Fang X, Ma T. Inhibition of TMEM16A expression suppresses growth and invasion in human colorectal cancer cells. PLoS One. 2014;9:e115443. Mokutani Y, Uemura M, Munakata K, Okuzaki D, Haraguchi N, Takahashi H, Nishimura J, Hata T, Murata K, Takemasa I, Mizushima T, Doki Y, Mori M, Yamamoto H. Down-regulation of microRNA-132 is associated with poor prognosis of colorectal cancer. Ann Surg Oncol. 2016; Shi ZZ, Shang L, Jiang YY, Hao JJ, Zhang Y, Zhang TT, Lin DC, Liu SG, Wang BS, Gong T, Zhan QM, Wang MR. Consistent and differential genetic aberrations between esophageal dysplasia and squamous cell carcinoma detected by array comparative genomic hybridization. Clin Cancer Res. 2013;19:5867–78. Jia L, Liu W, Guan L, Lu M, Wang K. Inhibition of calcium-activated Chloride Channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. PLoS One. 2015;10:e0136584. Deng L, Yang J, Chen H, Ma B, Pan K, Su C, Xu F, Zhang J. Knockdown of TMEM16A suppressed MAPK and inhibited cell proliferation and migration in hepatocellular carcinoma. Onco Targets Ther. 2016;9:325–33. Liu W, Lu M, Liu B, Huang Y, Wang K. Inhibition of ca(2+)-activated Cl(−) channel ANO1/TMEM16A expression suppresses tumor growth and invasiveness in human prostate carcinoma. Cancer Lett. 2012;326:41–51. Liu F, Cao QH, Lu DJ, Luo B, Lu XF, Luo RC, Wang XG. TMEM16A Overexpression contributes to tumor invasion and poor prognosis of human gastric cancer through TGF-beta signaling. Oncotarget. 2015;6:11585–99. Cao Q, Liu F, Ji K, Liu N, He Y, Zhang W, Wang L. MicroRNA-381 inhibits the metastasis of gastric cancer by targeting TMEM16A expression. J Exp Clin Cancer Res. 2017;36:29. Liu J, Liu Y, Ren Y, Kang L, Zhang L. Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-kappaB signaling pathway. Mol Med Rep. 2014;9:1068–74. Akervall JA, Jin Y, Wennerberg JP, Zatterstrom UK, Kjellen E, Mertens F, Willen R, Mandahl N, Heim S, Mitelman F. Chromosomal abnormalities involving 11q13 are associated with poor prognosis in patients with squamous cell carcinoma of the head and neck. Cancer. 1995;76:853–9. Ormandy CJ, Musgrove EA, Hui R, Daly RJ, Sutherland RL. Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat. 2003;78:323–35. Wanitchakool P, Wolf L, Koehl GE, Sirianant L, Schreiber R, Kulkarni S, Duvvuri U, Kunzelmann K. Role of anoctamins in cancer and apoptosis. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369:20130096. Scudieri P, Caci E, Bruno S, Ferrera L, Schiavon M, Sondo E, Tomati V, Gianotti A, Zegarra-Moran O, Pedemonte N, Rea F, Ravazzolo R, Galietta LJ. Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia. J Physiol. 2012;590:6141–55. Zhang XH, Zheng B, Yang Z, He M, Yue LY, Zhang RN, Zhang M, Zhang W, Zhang X, Wen JK. TMEM16A And Myocardin form a positive feedback loop that is disrupted by KLF5 during Ang II-induced vascular remodeling. Hypertension. 2015;66:412–21. Sun H, Xia Y, Paudel O, Yang XR, Sham JS. Chronic hypoxia-induced upregulation of Ca2+−activated Cl- channel in pulmonary arterial myocytes: a mechanism contributing to enhanced vasoreactivity. J Physiol. 2012;590:3507–21. Zhang A, Yan X, Li H, Gu Z, Zhang P, Zhang H, Li Y, Yu H. TMEM16A Protein attenuates lipopolysaccharide-mediated inflammatory response of human lung epithelial cell line A549. Exp Lung Res. 2014;40:237–50. Mazzone A, Gibbons SJ, Bernard CE, Nowsheen S, Middha S, Almada LL, Ordog T, Kendrick ML, Reid Lombardo KM, Shen KR, Galietta LJ, Fernandez-Zapico ME, Farrugia G. Identification and characterization of a novel promoter for the human ANO1 gene regulated by the transcription factor signal transducer and activator of transcription 6 (STAT6). FASEB J. 2015;29:152–63. Qin Y, Jiang Y, Sheikh AS, Shen S, Liu J, Jiang D. Interleukin-13 stimulates MUC5AC expression via a STAT6-TMEM16A-ERK1/2 pathway in human airway epithelial cells. Int Immunopharmacol. 2016;40:106–14. Zhang Y, Wang X, Wang H, Jiao J, Li Y, Fan E, Zhang L, Bachert C. TMEM16A-Mediated Mucin secretion in IL-13-induced nasal epithelial cells from chronic Rhinosinusitis patients. Allergy Asthma Immunol Res. 2015;7:367–75. Dmitrieva OS, Shilovskiy IP, Khaitov MR, Grivennikov SI. Interleukins 1 and 6 as main mediators of inflammation and cancer. Biochemistry (Mosc). 2016;81:80–90. Bharti R, Dey G, Mandal M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: a snapshot of IL-6 mediated involvement. Cancer Lett. 2016;375:51–61. May RD, Fung M. Strategies targeting the IL-4/IL-13 axes in disease. Cytokine. 2015;75:89–116. Suzuki A, Leland P, Joshi BH, Puri RK. Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine. 2015;75:79–88. Cha JY, Wee J, Jung J, Jang Y, Lee B, Hong GS, Chang BC, Choi YL, Shin YK, Min HY, Lee HY, Na TY, Lee MO, Oh U. Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia. Proc Natl Acad Sci U S A. 2015;112:9722–7. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17:630–41. Biswas S, Rao CM. Epigenetics in cancer: fundamentals and beyond. Pharmacol Ther. 2017; Shiwarski DJ, Shao C, Bill A, Kim J, Xiao D, Bertrand CA, Seethala RS, Sano D, Myers JN, Ha P, Grandis J, Gaither LA, Puthenveedu MA, Duvvuri U. To "grow" or "go": TMEM16A expression as a switch between tumor growth and metastasis in SCCHN. Clin Cancer Res. 2014;20:4673–88. Dixit R, Kemp C, Kulich S, Seethala R, Chiosea S, Ling S, Ha PK, Duvvuri U. TMEM16A/ANO1 Is differentially expressed in HPV-negative versus HPV-positive head and neck squamous cell carcinoma through promoter methylation. Sci Rep. 2015;5:16657. Zhang H, Shang YP, Chen HY, Li J. Histone deacetylases function as novel potential therapeutic targets for cancer. Hepatol Res. 2016; 10.1111/hepr.12757. Matsuba S, Niwa S, Muraki K, Kanatsuka S, Nakazono Y, Hatano N, Fujii M, Zhan P, Suzuki T, Ohya S. Downregulation of Ca2+−activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells. J Pharmacol Exp Ther. 2014;351:510–8. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22. Perez-Cornejo P, Gokhale A, Duran C, Cui Y, Xiao Q, Hartzell HC, Faundez V. Anoctamin 1 (Tmem16A) Ca2+−activated chloride channel stoichiometrically interacts with an ezrin-radixin-moesin network. Proc Natl Acad Sci U S A. 2012;109:10376–81. Steelman LS, Fitzgerald T, Lertpiriyapong K, Cocco L, Follo MY, Martelli AM, Neri LM, Marmiroli S, Libra M, Candido S, Nicoletti F, Scalisi A, Fenga C, Drobot L, Rakus D, Gizak A, Laidler P, Dulinska-Litewka J, Basecke J, Mijatovic S, Maksimovic-Ivanic D, Montalto G, Cervello M, Milella M, Tafuri A, Demidenko Z, Abrams SL, McCubrey JA. Critical roles of EGFR family members in breast cancer and breast cancer stem cells: targets for therapy. Curr Pharm Des. 2016;22:2358–88. Bill A, Gutierrez A, Kulkarni S, Kemp C, Bonenfant D, Voshol H, Duvvuri U, Gaither LA. ANO1 Interacts with EGFR and correlates with sensitivity to EGFR-targeting therapy in head and neck cancer. Oncotarget. 2015;6:9173–88. Jin X, Shah S, Liu Y, Zhang H, Lees M, Fu Z, Lippiat JD, Beech DJ, Sivaprasadarao A, Baldwin SA, Gamper N. Activation of the Cl- channel ANO1 by localized calcium signals in nociceptive sensory neurons requires coupling with the IP3 receptor. Sci Signal. 2013;6:ra73. Kunzelmann K, Cabrita I, Wanitchakool P, Ousingsawat J, Sirianant L, Benedetto R, Schreiber R. Modulating ca signals: a common theme for TMEM16, Ist2, and TMC. Pflugers Arch. 2016;468:475–90. Danielsson J, Perez-Zoghbi J, Bernstein K, Barajas MB, Zhang Y, Kumar S, Sharma PK, Gallos G, Emala CW. Antagonists of the TMEM16A calcium-activated Chloride Channel modulate airway smooth muscle tone and intracellular calcium. Anesthesiology. 2015;123:569–81. Cabrita I, Benedetto R, Fonseca A, Wanitchakool P, Sirianant L, Skryabin BV, Schenk LK, Pavenstadt H, Schreiber R, Kunzelmann K. Differential effects of anoctamins on intracellular calcium signals. FASEB J. 2017;31:2123–34. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90. Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer. 2013;12:86. Alberti C, Pinciroli P, Valeri B, Ferri R, Ditto A, Umezawa K, Sensi M, Canevari S, Tomassetti A. Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer. Oncogene. 2012;31:4139–49. Yang H, Huang LY, Zeng DY, Huang EW, Liang SJ, Tang YB, Su YX, Tao J, Shang F, Wu QQ, Xiong LX, Lv XF, Liu J, Guan YY, Zhou JG. Decrease of intracellular chloride concentration promotes endothelial cell inflammation by activating nuclear factor-kappaB pathway. Hypertension. 2012;60:1287–93. Buchholz B, Faria D, Schley G, Schreiber R, Eckardt KU, Kunzelmann K. Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst-forming epithelial cells. Kidney Int. 2014;85:1058–67. Stanich JE, Gibbons SJ, Eisenman ST, Bardsley MR, Rock JR, Harfe BD, Ordog T, Farrugia G. Ano1 As a regulator of proliferation. Am J Physiol Gastrointest Liver Physiol. 2011;301:G1044–51. Sauter DR, Novak I, Pedersen SF, Larsen EH, Hoffmann EK. ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC). Pflugers Arch. 2015;467:1495–508. Simon S, Grabellus F, Ferrera L, Galietta L, Schwindenhammer B, Muhlenberg T, Taeger G, Eilers G, Treckmann J, Breitenbuecher F, Schuler M, Taguchi T, Fletcher JA, Bauer S. DOG1 Regulates growth and IGFBP5 in gastrointestinal stromal tumors. Cancer Res. 2013;73:3661–70. Ubby I, Bussani E, Colonna A, Stacul G, Locatelli M, Scudieri P, Galietta L, Pagani F. TMEM16A Alternative splicing coordination in breast cancer. Mol Cancer. 2013;12:75. Wu H, Wang H, Guan S, Zhang J, Chen Q, Wang X, Ma K, Zhao P, Zhao H, Yao W, Jin F, Xiao Q, Wei M. Cell-specific regulation of proliferation by Ano1/TMEM16A in breast cancer with different ER, PR, and HER2 status. Oncotarget. 2017; Lee YS, Lee JK, Bae Y, Lee BS, Kim E, Cho CH, Ryoo K, Yoo J, Kim CH, Yi GS, Lee SG, Lee CJ, Kang SS, Hwang EM, Park JY. Suppression of 14-3-3gamma-mediated surface expression of ANO1 inhibits cancer progression of glioblastoma cells. Sci Rep. 2016;6:26413. Li Y, Zhang J, Hong S. ANO1 As a marker of oral squamous cell carcinoma and silencing ANO1 suppresses migration of human SCC-25 cells. Med Oral Patol Oral Cir Bucal. 2014;19:e313–9. Ruffin M, Voland M, Marie S, Bonora M, Blanchard E, Blouquit-Laye S, Naline E, Puyo P, Le Rouzic P, Guillot L, Corvol H, Clement A, Tabary O. Anoctamin 1 dysregulation alters bronchial epithelial repair in cystic fibrosis. Biochim Biophys Acta. 1832;2013:2340–51. Jacobsen KS, Zeeberg K, Sauter DR, Poulsen KA, Hoffmann EK, Schwab A. The role of TMEM16A (ANO1) and TMEM16F (ANO6) in cell migration. Pflugers Arch. 2013;465:1753–62. Kunzelmann K, Tian Y, Martins JR, Faria D, Kongsuphol P, Ousingsawat J, Thevenod F, Roussa E, Rock J, Schreiber R. Anoctamins. Pflugers Arch. 2011;462:195–208. Schwab A, Fabian A, Hanley PJ, Stock C. Role of ion channels and transporters in cell migration. Physiol Rev. 2012;92:1865–913. Lee YS, Bae Y, Park N, Yoo JC, Cho CH, Ryoo K, Hwang EM, Park JY. Surface expression of the Anoctamin-1 (ANO1) channel is suppressed by protein-protein interactions with beta-COP. Biochem Biophys Res Commun. 2016;475:216–22. Ha JR, Siegel PM, Ursini-Siegel J. The tyrosine Kinome dictates breast cancer heterogeneity and therapeutic responsiveness. J Cell Biochem. 2016;117:1971–90. Fleuren ED, Zhang L, Wu J, Daly RJ. The kinome 'at large' in cancer. Nat Rev Cancer. 2016;16:83–98. Ponuwei GA. A glimpse of the ERM proteins. J Biomed Sci. 2016;23:35. Clucas J, Valderrama F. ERM proteins in cancer progression. J Cell Sci. 2015;128:1253. Huang X, Godfrey TE, Gooding WE, McCarty KS Jr, Gollin SM. Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma. Genes Chromosomes Cancer. 2006;45:1058–69. Namkung W, Phuan PW, Verkman AS. TMEM16A Inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J Biol Chem. 2011;286:2365–74. De La Fuente R, Namkung W, Mills A, Verkman AS. Small-molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel. Mol Pharmacol. 2008;73:758–68. Kulkarni S, Bill A, Godse NR, Khan NI, Kass JI, Steehler K, Kemp C, Davis K, Bertrand CA, Vyas AR, Holt DE, Grandis JR, Gaither LA, Duvvuri U. TMEM16A/ANO1 Suppression improves response to antibody mediated targeted therapy of EGFR and HER2/ERBB2. Genes Chromosomes Cancer. 2017; Seo Y, Ryu K, Park J, Jeon DK, Jo S, Lee HK, Namkung W. Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells. PLoS One. 2017;12:e0174935. Bill A, Hall ML, Borawski J, Hodgson C, Jenkins J, Piechon P, Popa O, Rothwell C, Tranter P, Tria S, Wagner T, Whitehead L, Gaither LA. Small molecule-facilitated degradation of ANO1 protein: a new targeting approach for anticancer therapeutics. J Biol Chem. 2014;289:11029–41. Gianotti A, Ferrera L, Philp AR, Caci E, Zegarra-Moran O, Galietta LJ, Flores CA. Pharmacological analysis of epithelial chloride secretion mechanisms in adult murine airways. Eur J Pharmacol. 2016;781:100–8. Liu Y, Zhang H, Huang D, Qi J, Xu J, Gao H, Du X, Gamper N. Characterization of the effects of Cl(−) channel modulators on TMEM16A and bestrophin-1 ca(2)(+) activated Cl(−) channels. Pflugers Arch. 2015;467:1417–30. Kucherenko YV, Wagner-Britz L, Bernhardt I, Lang F. Effect of chloride channel inhibitors on cytosolic Ca2+ levels and Ca2+−activated K+ (Gardos) channel activity in human red blood cells. J Membr Biol. 2013;246:315–26. Kunzelmann K, Schreiber R, Kmit A, Jantarajit W, Martins JR, Faria D, Kongsuphol P, Ousingsawat J, Tian Y. Expression and function of epithelial anoctamins. Exp Physiol. 2012;97:184–92. Hiraoka K, Miyazaki H, Niisato N, Iwasaki Y, Kawauchi A, Miki T, Marunaka Y. Chloride ion modulates cell proliferation of human androgen-independent prostatic cancer cell. Cell Physiol Biochem. 2010;25:379–88. Habela CW, Ernest NJ, Swindall AF, Sontheimer H. Chloride accumulation drives volume dynamics underlying cell proliferation and migration. J Neurophysiol. 2009;101:750–7. Duran C, Thompson CH, Xiao Q, Hartzell HC. Chloride channels: often enigmatic, rarely predictable. Annu Rev Physiol. 2010;72:95–121. Ohsawa R, Miyazaki H, Niisato N, Shiozaki A, Iwasaki Y, Otsuji E, Marunaka Y. Intracellular chloride regulates cell proliferation through the activation of stress-activated protein kinases in MKN28 human gastric cancer cells. J Cell Physiol. 2010;223:764–70. Shang L, Hao JJ, Zhao XK, He JZ, Shi ZZ, Liu HJ, Wu LF, Jiang YY, Shi F, Yang H, Zhang Y, Liu YZ, Zhang TT, Xu X, Cai Y, Jia XM, Li M, Zhan QM, Li EM, Wang LD, Wei WQ, Wang MR. ANO1 Protein as a potential biomarker for esophageal cancer prognosis and precancerous lesion development prediction. Oncotarget. 2016; Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montgomery K, Varma S, Corless CL, Heinrich MC, Smith KS, Wang Z, Rubin B, Nielsen TO, Seitz RS, Ross DT, West RB, Cleary ML, van de Rijn M. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 2008;32:210–8. Reddy RB, Bhat AR, James BL, Govindan SV, Mathew R, Ravindra DR, Hedne N, Illiayaraja J, Kekatpure V, Khora SS, Hicks W, Tata P, Kuriakose MA, Suresh A. Meta-analyses of microarray datasets identifies ANO1 and FADD as prognostic markers of head and neck cancer. PLoS One. 2016;11:e0147409. Li Q, Zhi X, Zhou J, Tao R, Zhang J, Chen P, Roe OD, Sun L, Ma L. Circulating tumor cells as a prognostic and predictive marker in gastrointestinal stromal tumors: a prospective study. Oncotarget. 2016; Ferrera L, Caputo A, Galietta LJ. TMEM16A Protein: a new identity for ca(2+)-dependent Cl(−) channels. Physiology (Bethesda). 2010;25:357–63. Takayama Y, Shibasaki K, Suzuki Y, Yamanaka A, Tominaga M. Modulation of water efflux through functional interaction between TRPV4 and TMEM16A/anoctamin 1. FASEB J. 2014;28:2238–48. Gao da Y, Zhang BL, Leung MC, Au SC, Wong PY, Shum WW. Coupling of TRPV6 and TMEM16A in epithelial principal cells of the rat epididymis. J Gen Physiol. 2016;148:161–82. Sun Y, Birnbaumer L, Singh BB. TRPC1 Regulates calcium-activated chloride channels in salivary gland cells. J Cell Physiol. 2015;230:2848–56. Viitanen TM, Sukumaran P, Lof C, Tornquist K. Functional coupling of TRPC2 cation channels and the calcium-activated anion channels in rat thyroid cells: implications for iodide homeostasis. J Cell Physiol. 2013;228:814–23. Wang Q, Leo MD, Narayanan D, Kuruvilla KP, Jaggar JH. Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries. Am J Physiol Cell Physiol. 2016; 10.1152/ajpcell.00092.2016. Mercer AJ, Rabl K, Riccardi GE, Brecha NC, Stella SL Jr, Thoreson WB. Location of release sites and calcium-activated chloride channels relative to calcium channels at the photoreceptor ribbon synapse. J Neurophysiol. 2011;105:321–35. Horvath B, Vaczi K, Hegyi B, Gonczi M, Dienes B, Kistamas K, Banyasz T, Magyar J, Baczko I, Varro A, Seprenyi G, Csernoch L, Nanasi PP, Szentandrassy N. Sarcolemmal Ca2+−entry through L-type Ca2+ channels controls the profile of Ca2+−activated Cl- current in canine ventricular myocytes. J Mol Cell Cardiol. 2016;97:125–39. Concepcion AR, Vaeth M, Wagner LE 2nd, Eckstein M, Hecht L, Yang J, Crottes D, Seidl M, Shin HP, Weidinger C, Cameron S, Turvey SE, Issekutz T, Meyts I, Lacruz RS, Cuk M, Yule DI, Feske S. Store-operated Ca2+ entry regulates Ca2+−activated chloride channels and eccrine sweat gland function. J Clin Invest. 2016;126:4303–18. Oh SJ, Hwang SJ, Jung J, Yu K, Kim J, Choi JY, Hartzell HC, Roh EJ, Lee CJ. MONNA, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1. Mol Pharmacol. 2013;84:726–35. Yao Z, Namkung W, Ko EA, Park J, Tradtrantip L, Verkman AS. Fractionation of a herbal antidiarrheal medicine reveals eugenol as an inhibitor of Ca2+−activated Cl- channel TMEM16A. PLoS One. 2012;7:e38030. Sui Y, Wu F, Lv J, Li H, Li X, Du Z, Sun M, Zheng Y, Yang L, Zhong L, Zhang X, Zhang G. Identification of the novel TMEM16A inhibitor Dehydroandrographolide and its anticancer activity on SW620 cells. PLoS One. 2015;10:e0144715. Burris SK, Wang Q, Bulley S, Neeb ZP, Jaggar JH. 9-Phenanthrol inhibits recombinant and arterial myocyte TMEM16A channels. Br J Pharmacol. 2015;172:2459–68. Seo Y, Lee HK, Park J, Jeon DK, Jo S, Jo M, Namkung W. Ani9, A novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2. PLoS One. 2016;11:e0155771. Seo Y, Park J, Kim M, Lee HK, Kim JH, Jeong JH, Namkung W. Inhibition of ANO1/TMEM16A Chloride Channel by Idebenone and its Cytotoxicity to cancer cell lines. PLoS One. 2015;10:e0133656. Tian Y, Schreiber R, Wanitchakool P, Kongsuphol P, Sousa M, Uliyakina I, Palma M, Faria D, Traynor-Kaplan AE, Fragata JI, Amaral MD, Kunzelmann K. Control of TMEM16A by INO-4995 and other inositolphosphates. Br J Pharmacol. 2013;168:253–65. Boedtkjer DM, Kim S, Jensen AB, Matchkov VM, Andersson KE. New selective inhibitors of calcium-activated chloride channels - T16Ainh -A01, CaCCinh -A01 and MONNA - what do they inhibit? Br J Pharmacol. 2015;172:4158–72.