title: Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma.
abstract: Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC.
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Texas, USA.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Xu
authors.affiliation: Laboratory of Research Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pancreato-Billary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Baogang
authors.initials: B
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Minhu
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Sui
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.|Department of Medical Ultrasound, Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Kuang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C553458:apatinib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: PI3K; VEGFR2; apatinib; apoptosis; intrahepatic cholangiocarcinoma