Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway

// Haiyong Wang 1, 2, * , Chenyue Zhang 1, 3, * , Litao Xu 1, 3 , Kun Zang 1, 3 , Zhouyu Ning 1, 3 , Feng Jiang 4 , Huiying Chi 5 , Xiaoyan Zhu 1, 3 , Zhiqiang Meng 1, 3 1 Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2 Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Jinan, 250117, China 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 4 Department of Integrative Oncology, Zhucheng Hospital of TCM, Zhucheng 262200, China 5 Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China * These authors contributed equally to this work Correspondence to: Xiaoyan Zhu, e-mail: zhuxiaoyanx@126.com Zhiqiang Meng, e-mail: mengzhq@gmail.com Keywords: bufalin, metastasis, HIF-1α, hepatocellular carcinoma, PI3K/AKT/mTOR Received: July 20, 2015      Accepted: January 06, 2016      Published: March 06, 2016 ABSTRACT It has been reported that there are multiple mechanisms by which bufalin could exert its antimetastatic effect. HIF-1α has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether bufalin could exert the antimetastatic effect by modulating HIF-1α expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of bufalin in vivo and in vitro . Our results demonstrated that the liver/lung metastases were significantly reduced in bufalin-treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with bufalin. Moreover, the transforming growth factor-β1 (TGF-β1)-induced EMT was also abrogated by bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1α (HIF-1α) played an important role in the antimetastatic effect of bufalin in hepatocellular carcinoma. Importantly, HIF-1α expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1α axis.