title: Identification of sphingosine kinase 1 (SphK1) as a primary target of icaritin in hepatocellular carcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is a highly aggressive neoplasm. We aim to explore the anti-HCC activity by a natural prenylflavonoid icaritin. Icaritin was cytotoxic and pro-apoptotic when added to established (HepG2, KYN-2 and Huh-7 lines) and primary human HCC cells. At the signaling level, icaritin inhibited sphingosine kinase 1 (SphK1) activity in HCC cells, which led to pro-apoptotic ceramide production and JNK1 activation. SphK1 inhibition or silence (by shRNA/microRNA) mimicked icaritin-mediated cytotoxicity, and almost nullified icaritin's activity in HepG2 cells. Reversely, exogenous over-expression of SphK1 sensitized icaritin-induced HepG2 cell apoptosis. In vivo, oral administration of icaritin dramatically inhibited HepG2 xenograft growth in SCID mice. Further, SphK1 activity in icaritin-treated tumors was largely inhibited. In summary, icaritin exerts potent anti-HCC activity in vitro and in vivo. SphK1 inhibition could be the primary mechanism of its actions in HCC cells.
authors.affiliation: Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.|Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Lu
authors.affiliation: Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China.
authors.forename: Min-Bin
authors.initials: MB
authors.lastname: Chen
authors.affiliation: Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Mian-Hua
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Li
authors.affiliation: Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Mu-Xin
authors.initials: MX
authors.lastname: Wei
authors.affiliation: Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Liu
authors.affiliation: People's Liberation Army Cancer Center, 81st Hospital of People's Liberation Army, Nanjing, China.
authors.forename: Shu-Kui
authors.initials: SK
authors.lastname: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D014408:Biomarkers, Tumor; D002518:Ceramides; D005419:Flavonoids; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C499403:icaritin
keywords: hepatocellular carcinoma (HCC); icaritin; sphingosine kinase 1 (SphK1) and ceramide