title: SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway.
abstract: OBJECTIVE
  Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown.
  
  
  METHODS
  The expressions of β-catenin and related molecules of Wnt/β-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of β-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay.
  
  
  RESULTS
  We found that SKI II decreased the expression of β-catenin and the downstream molecules of β-catenin signal pathway and promotes the β-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered β-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of β-catenin and downstream molecules of β-catenin signal pathway.
  
  
  CONCLUSIONS
  SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated β-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells.
authors.affiliation: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, PR China.
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, PR China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: He
authors.affiliation: China Astronaut Research and Training Centre, 26# Beiqing Road, Beijing 100094, PR China.
authors.forename: Jia-Ping
authors.initials: JP
authors.lastname: Wang
authors.affiliation: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, PR China. Electronic address: shaor@imb.pumc.edu.cn.
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000071818:Wnt-5a Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000099157:Sphingosine Kinase; C495270:CTNNB1 protein, human; C085389:WNT5A protein, human
keywords: Cell proliferation; Hepatocellular carcinoma; SKI II; Sphingosine kinase; Wnt signaling pathway; Wnt5A protein