title: Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells.
abstract: Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and upregulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth-suppressive effects on these cell lines via inhibition of p-Akt activity and the Bcl-2 family. Notably, either dysfunction or downregulation of CLIC1 can partially decrease the antineoplastic effects of metformin while upregulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma.
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yongchen
authors.identifier: http://orcid.org/0000-0002-1772-5572
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Maolan
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yichi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shili
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fatao
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yijian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018118:Chloride Channels / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C501966:CLIC1 protein, human; D018118:Chloride Channels; D019253:Proto-Oncogene Proteins c-bcl-2; D008687:Metformin; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; chloride intracellular channel 1; gallbladder carcinoma; metformin; proliferation