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Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling.
- Source :
-
Pharmacological reports : PR [Pharmacol Rep] 2015 Apr; Vol. 67 (2), pp. 388-93. Date of Electronic Publication: 2014 Nov 05. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br />Conclusion: 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.<br /> (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)
- Subjects :
- Alkaloids antagonists & inhibitors
Caspase 3 metabolism
Caspase 9 metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Cytochromes c metabolism
Dose-Response Relationship, Drug
Drugs, Chinese Herbal pharmacology
Humans
Janus Kinase 2 metabolism
Membrane Potential, Mitochondrial drug effects
Mutation
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Oligopeptides pharmacology
Quinolizines antagonists & inhibitors
STAT3 Transcription Factor genetics
STAT3 Transcription Factor metabolism
Matrines
Alkaloids pharmacology
Antineoplastic Agents pharmacology
Apoptosis drug effects
Cholangiocarcinoma pathology
Janus Kinase 2 antagonists & inhibitors
Quinolizines pharmacology
STAT3 Transcription Factor antagonists & inhibitors
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2299-5684
- Volume :
- 67
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Pharmacological reports : PR
- Publication Type :
- Academic Journal
- Accession number :
- 25712669
- Full Text :
- https://doi.org/10.1016/j.pharep.2014.10.016