title: Blockade of four-transmembrane L6 family member 5 (TM4SF5)-mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative.
abstract: We previously reported that the four-transmembrane L6 family member 5 (TM4SF5) was highly expressed in hepatocarcinoma, induced morphological elongation and epithelial-mesenchymal transition, and caused abnormal cell growth in multilayers in vitro and tumor formation in vivo. In this study, we identified a synthetic compound, 4'-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC) that antagonized both the TM4SF5-mediated multilayer growth and TM4SF5-enhanced migration/invasion. TSAHC treatment induced multilayer-growing cells to grow in monolayers, recovering contact inhibition without accompanying apoptosis, and inhibited chemotactic migration and invasion. Tumor formation in nude mice injected with TM4SF5-expressing cells and the growth of cells expressing endogenous TM4SF5, but not of TM4SF5-null cells, was suppressed by treatment with TSAHC, but not by treatment with its analogs. The structure-activity relationship indicated the significance of 4'-p-toluenesulfonylamido and 4-hydroxy groups for the anti-TM4SF5 effects of TSAHC. Point mutations of the putative N-glycosylation sites abolished the TM4SF5-specific TSAHC responsiveness.
  
  
  CONCLUSIONS
  These observations suggest that TM4SF5-enhanced tumorigenic proliferation and metastatic potential can be blocked by TSAHC, likely through targeting the extracellular region of TM4SF5, which is important for protein-protein interactions.
authors.affiliation: Cancer Research Institute, College of Medicine, Cell Dynamics Research Center, Seoul National University, Seoul, Korea.
authors.forename: Sin-Ae
authors.initials: SA
authors.lastname: Lee
authors.forename: Hyung Won
authors.initials: HW
authors.lastname: Ryu
authors.forename: Young Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Suyong
authors.initials: S
authors.lastname: Choi
authors.forename: Mi Ji
authors.initials: MJ
authors.lastname: Lee
authors.forename: Tae Kyoung
authors.initials: TK
authors.lastname: Kwak
authors.forename: Hyeon Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Moonjae
authors.initials: M
authors.lastname: Cho
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D047188:Chalcones / Q000494:pharmacology*; D003260:Contact Inhibition / Q000187:drug effects; D006031:Glycosylation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D010641:Phenotype; D017354:Point Mutation; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C540441:4'-(4-toluenesulfonylamido)-4-hydroxychalcone; D047188:Chalcones; D008565:Membrane Proteins; D013449:Sulfonamides; C111029:TM4SF5 protein, human; D002599:Chalcone