title: Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway.
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.
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Jinan, 250117, China.
authors.forename: Haiyong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Chenyue
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Litao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zang
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhouyu
authors.initials: Z
authors.lastname: Ning
authors.affiliation: Department of Integrative Oncology, Zhucheng Hospital of TCM, Zhucheng 262200, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Chi
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Meng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D002018:Bufanolides / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002018:Bufanolides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; C497442:HIF1A protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human; C022777:bufalin
keywords: HIF-1α; PI3K/AKT/mTOR; bufalin; hepatocellular carcinoma; metastasis