title: ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC).
abstract: Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca(2+)-activated Cl(-) channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological function has only been poorly understood. The aim of the present study is to establish the significance of ANO1 in PDAC behavior and demarcate its roles in PDAC from those of the volume-regulated anion channel (VRAC). We performed qPCR and Western blot measurements on different PDAC cell lines (Panc-1, Mia PaCa 2, Capan-1, AsPC-1, BxPC-3) and compared the results to those obtained in a human pancreatic ductal epithelium (HPDE) cell line. All cancer cell lines showed an upregulation of ANO1 on mRNA and protein levels. Whole-cell patch-clamp recordings identified large Ca(2+) and voltage-dependent Cl(-) currents in PDAC cells. Using siRNA knockdown of ANO1 and three ANO1 inhibitors (T16Ainh-A01, CaCCinh-A01, and NS3728), we found that ANO1 is the main constituent of CaCC current in PDAC cells. We further characterized these three inhibitors and found that they had unspecific effects on the free intracellular calcium concentration. Functional studies on PDAC behavior showed that surprisingly inhibition of ANO1 did not influence cellular proliferation. On the other hand, we found ANO1 channel to be pivotal in PDAC cell migration as assessed in wound healing experiments.
authors.affiliation: Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen Ø, Denmark. Daniel.Sauter@bio.ku.dk.
authors.forename: D R P
authors.initials: DRP
authors.lastname: Sauter
authors.affiliation: Section for Molecular Integrative Physiology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.
authors.forename: I
authors.initials: I
authors.lastname: Novak
authors.affiliation: Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen Ø, Denmark.
authors.forename: S F
authors.initials: SF
authors.lastname: Pedersen
authors.affiliation: Section for Molecular Integrative Physiology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.
authors.forename: E H
authors.initials: EH
authors.lastname: Larsen
authors.affiliation: Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen Ø, Denmark.
authors.forename: E K
authors.initials: EK
authors.lastname: Hoffmann
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000075369:Anoctamin-1; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D002712:Chlorides; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D002118:Calcium