Premium
Blockade of four‐transmembrane L6 family member 5 (TM4SF5)‐mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative
Author(s) -
Lee SinAe,
Ryu Hyung Won,
Kim Young Mee,
Choi Suyong,
Lee Mi Ji,
Kwak Tae Kyoung,
Kim Hyeon Jung,
Cho Moonjae,
Park Ki Hun,
Lee Jung Weon
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22777
Subject(s) - biology , transmembrane protein , motility , cell growth , chalcone , apoptosis , in vitro , cell culture , in vivo , extracellular , microbiology and biotechnology , cancer research , cell migration , receptor , biochemistry , chemistry , genetics , stereochemistry
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 ‐ t oluene s ulfonyl a mido)‐4‐ h ydroxy c halcone (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. Conclusion: 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. (H EPATOLOGY 2009.)