title: Identification of the Novel TMEM16A Inhibitor Dehydroandrographolide and Its Anticancer Activity on SW620 Cells.
abstract: TMEM16A, a calcium-activated chloride channel (CaCC), is highly amplified and expressed in human cancers and is involved in the growth and metastasis of some malignancies. Inhibition of TMEM16A represents a novel pharmaceutical approach for the treatment of cancers and metastases. The purpose of this study is to identify a new TMEM16A inhibitor, investigate the effects of this inhibitor on the proliferation and metastasis of TMEM16A-amplified SW620 cells, and to elucidate the underlying molecular mechanism in vitro. We identified a novel small-molecule TMEM16A inhibitor dehydroandrographolide (DP). By using patch clamp electrophysiology, we showed that DP inhibited TMEM16A chloride currents in Fisher rat thyroid (FRT) cells that were transfected stably with human TMEM16A and in TMEM16A-overexpressed SW620 cells but did not alter cystic fibrosis transmembrane conductance regulator (CFTR) chloride currents. Further functional studies showed that DP suppressed the proliferation of SW620 cells in a dose- and time-dependent manner using MTT assays. Moreover, DP significantly inhibited migration and invasion of SW620 cells as detected by wound-healing and transwell assays. Further mechanistic study demonstrated that knockdown of human TMEM16A decreased the inhibitory effect of DP on the proliferation of SW620 cells and that TMEM16A-dependent cells (SW620 and HCT116) were more sensitive to DP than TMEM16A-independent cells (SW480 and HCT8). In addition, we found that treatment of SW620 cells with DP led to a decrease in TMEM16A protein levels but had no effect on TMEM16A mRNA levels. The current work reveals that DP, a novel TMEM16A inhibitor, exerts its anticancer activity on SW620 cells partly through a TMEM16A-dependent mechanism, which may introduce a new targeting approach for an antitumour therapy in TMEM16A-amplified cancers.
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sui
authors.affiliation: Department of Gynecology and Obstetrics, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Radiology, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Lv
authors.affiliation: Department of Dermatology, Jilin University Bethune First Hospital, Changchun, P. R. China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Zhenwu
authors.initials: Z
authors.lastname: Du
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Sun
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Longfei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Department of Thoracic Surgery, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Xingyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Molecular and Chemical Genetics of Critical Human Diseases of Jilin Province, Jilin University Bethune Second Hospital, Changchun, P. R. China.
authors.forename: Guizhen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D017136:Ion Transport; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland; D019076:Transgenes
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D000970:Antineoplastic Agents; C505032:CFTR protein, human; D002121:Calcium Channel Blockers; D018118:Chloride Channels; D004224:Diterpenes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002118:Calcium; C478098:dehydroandrographolide