title: FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression.
abstract: Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC.
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Chu
authors.affiliation: The Wistar Institute, Philadelphia, PA, 19104, USA.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
authors.forename: Mohan
authors.initials: M
authors.lastname: Man
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001659:Biliary Tract / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005706:Gallbladder Neoplasms / Q000188:drug therapy*; D006801:Humans; D033862:Iron-Binding Proteins / Q000819:agonists*; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis*; D000096923:Frataxin
chemical_list: D000970:Antineoplastic Agents; D002635:Chenodeoxycholic Acid; D002945:Cisplatin; D033862:Iron-Binding Proteins; D007555:Isoxazoles; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D050796:STAT3 Transcription Factor; D051020:bcl-X Protein; D000096923:Frataxin; C494811:BCL2L1 protein, human; C494086:STAT3 protein, human; C509249:PTPN6 protein, human; C412815:GW 4064
keywords: biliary tract cancer; cisplatin; farnesoid X receptor; signal transducer and activators of transcription 3; small heterodimer partner