Blockade of four-transmembrane L6 family member 5 (TM4SF5)-mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative.
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.
Lee
Sin-Ae
SA
Cancer Research Institute, College of Medicine, Cell Dynamics Research Center, Seoul National University, Seoul, Korea.
Ryu
Hyung Won
HW
Kim
Young Mee
YM
Choi
Suyong
S
Lee
Mi Ji
MJ
Kwak
Tae Kyoung
TK
Kim
Hyeon Jung
HJ
Cho
Moonjae
M
Park
Ki Hun
KH
Lee
Jung Weon
JW
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*
C540441:4'-(4-toluenesulfonylamido)-4-hydroxychalcone; D047188:Chalcones; D008565:Membrane Proteins; D013449:Sulfonamides; C111029:TM4SF5 protein, human; D002599:Chalcone