title: Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling.
abstract: BACKGROUND
  Constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling contributes to apoptosis resistance in cholangiocarcinoma. The aim of this study is to check whether matrine, an alkaloid isolated from traditional Chinese herb Sophora flavescens ait, can exert cytotoxic effects against cholangiocarcinoma cells via inactivation of STAT3 signaling.
  
  
  METHODS
  Mz-ChA-1 and KMCH-1 cholangiocarcinoma cells were treated with matrine at 0.25-2.0 g/L for 48 h and cell viability and apoptosis were assessed. Apoptosis-related molecular changes and STAT3 phosphorylation and transcriptional activities were measured after matrine treatment for 48 h. The effect of expression of a constitutively active STAT3 mutant on matrine-induced apoptosis was determined.
  
  
  RESULTS
  Matrine significantly inhibited the viability and induced apoptosis in cholangiocarcinoma cells. Matrine treatment caused loss of mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-9 and -3. Matrine-induced apoptosis was inhibited in the presence of the caspase-3 inhibitor Ac-DEVD-CHO. Matrine reduced the phosphorylation levels of Janus kinase 2 (JAK2) and STAT3, inhibited STAT3-dependent transcriptional activity, and downregulated STAT3 target gene Mcl-1. Notably, expression of the constitutively active form of STAT3 significantly antagonized matrine-induced apoptosis of cholangiocarcinoma cells.
  
  
  CONCLUSIONS
  Matrine can trigger mitochondrial apoptotic death of cholangiocarcinoma cells largely through inhibition of JAK2/STAT3 signaling. Therefore, matrine represents a potentially effective anticancer agent for cholangiocarcinoma.
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Nanmu
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. Electronic address: cuihong_dr@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Jinxi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Anesthesia, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Jinxue
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000470:Alkaloids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011807:Quinolizines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009842:Oligopeptides; D011807:Quinolizines; D050796:STAT3 Transcription Factor; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D045304:Cytochromes c; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3; D053453:Caspase 9; D000093842:Matrines
keywords: Apoptosis; Mcl-1; Phytochemical; STAT3 signaling; Therapy