title: CFTR chloride channel is a molecular target of the natural cancer preventive agent resveratrol.
abstract: The naturally occurring polyphenol compound resveratrol (RES) has been receiving wide attention because of its variety of health benefits and favourable biological activities. Previous studies have shown that RES could induce intestinal chloride secretion in mouse jejunum and stimulate cAMP-dependent Cl- secretion in T84, primary cultured murine nasal septal and human sinonasal epithelial cells, but the precise molecular target is not clear. We therefore tested the hypothesis that RES may stimulate the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Using cell-based fluorescent assays, transepithelial short-circuit current measurements and excised inside-out patch-clamp analysis; we found that RES dose-dependently potentiate CFTR Cl- channel activities, which was reversed by CFTR inhibitors CFTR(inh)-172 and GlyH101. Transepithelial Cl- secretion by CFTR-expressing FRT cells was stimulated by RES with half maximal concentration -80 microM. Intracellular cAMP content was not elevated by RES in FRT cells. Excised inside-out patch-clamp analysis indicated that RES significantly increased the chloride currents of CFTR. In ex vivo studies, RES stimulated the transmucosal chloride current of rat colon by short-circuit current assay. These data suggested that CFTR is a molecular target of RES. Our findings add a new molecular target to RES, and RES may represent a novel class of therapeutic lead compounds in treating CFTR-related diseases including CF and habitual constipation.
authors.affiliation: School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, PR China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.forename: B O
authors.initials: BO
authors.lastname: Yu
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sui
authors.forename: Yaofang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Shuguang
authors.initials: S
authors.lastname: Hou
authors.forename: Tonghui
authors.initials: T
authors.lastname: Ma
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D015194:Diffusion Chambers, Culture; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014162:Transfection
chemical_list: D016588:Anticarcinogenic Agents; D018076:DNA, Complementary; D013267:Stilbenes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D000077185:Resveratrol