Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma

// Hong Peng 1, * , Qiuyang Zhang 2, * , Jiali Li 1, * , Ning Zhang 3 , Yunpeng Hua 1 , Lixia Xu 3 , Yubin Deng 4 , Jiaming Lai 5 , Zhenwei Peng 6 , Baogang Peng 1 , Minhu Chen 3 , Sui Peng 3 , Ming Kuang 1, 7 1 Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 2 Department of Internal Medicine, The University of Texas Southwestern Medical School, Dallas, Texas, USA 3 Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 4 Laboratory of Research Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 5 Department of Pancreato-Billary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 6 Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 7 Department of Medical Ultrasound, Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China * These authors have contributed equally to this work. Correspondence to: Sui Peng, e-mail: pengsui@vip.163.com Ming Kuang, e-mail: kuangminda@hotmail.com Keywords: intrahepatic cholangiocarcinoma, VEGFR2, apatinib, apoptosis, PI3K Received: October 18, 2015     Accepted: February 06, 2016     Published: March 07, 2016 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.