TY - JOUR
T1 - An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3
AU - Kizuka, Yasuhiko
AU - Nakano, Miyako
AU - Yamaguchi, Yoshiki
AU - Nakajima, Kazuki
AU - Oka, Ritsuko
AU - Sato, Keiko
AU - Ren, Chien Tai
AU - Hsu, Tsui Ling
AU - Wong, Chi Huey
AU - Taniguchi, Naoyuki
N1 - Funding Information:
We would like to thank Ms. Fumi Ota (Disease Glycomics Team, RIKEN) for making the FUT8 construct. We also thank Dr. Masamichi Nagae (University of Tokyo) for valuable discussion. This work was supported by RIKEN (Systems Glycobiology Research project to N.T.), by the project for utilizing glycans in the development of innovative drug discovery technologies from the Japan Agency for Medical Research and Development (AMED) to Y.K., by the Japan Society for the Promotion of Science (Grant-in-Aid for Challenging Exploratory Research to N.T. [grant number 15K14481 ] and Y.K. [ 26670148 ], Grant-in-Aid for Scientific Research (B) to N.T. [grant number 15H04700 ], and Grant-in-Aid for Scientific Research on Innovative Areas to Y.K. [grant number 26110723 ]), and by Takeda Science Foundation .
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/12/21
Y1 - 2017/12/21
N2 - Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-Alk-Fuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc). The action mechanism was shown to deplete cellular GDP-Fuc, and the direct target of 6-Alk-Fuc is FX (encoded by TSTA3), the bifunctional GDP-Fuc synthase. We also show that 6-Alk-Fuc halts hepatoma invasion. These results highlight the unappreciated role of 6-Alk-Fuc as a fucosylation inhibitor and its potential use for basic and clinical science. Fucose sugar is involved in cancer and inflammation. Kizuka et al. found that a fucose alkyne strongly inhibits cellular fucosylation. The compound selectively inhibits GDP-fucose synthetase FX and can be applied to glycan-related diseases.
AB - Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-Alk-Fuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc). The action mechanism was shown to deplete cellular GDP-Fuc, and the direct target of 6-Alk-Fuc is FX (encoded by TSTA3), the bifunctional GDP-Fuc synthase. We also show that 6-Alk-Fuc halts hepatoma invasion. These results highlight the unappreciated role of 6-Alk-Fuc as a fucosylation inhibitor and its potential use for basic and clinical science. Fucose sugar is involved in cancer and inflammation. Kizuka et al. found that a fucose alkyne strongly inhibits cellular fucosylation. The compound selectively inhibits GDP-fucose synthetase FX and can be applied to glycan-related diseases.
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U2 - 10.1016/j.chembiol.2017.08.023
DO - 10.1016/j.chembiol.2017.08.023
M3 - Article
C2 - 29033318
AN - SCOPUS:85031296302
VL - 24
SP - 1467-1478.e5
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 12
ER -