AsianScientist (Oct. 19, 2017) – Researchers at the RIKEN Global Research Cluster in Japan have discovered a sweet way to prevent the spread of cancer in the liver. Their findings are published in Cell Chemical Biology.
Many important biological functions depend on a process called glycosylation, which is the attachment of sugars to other molecules such as proteins, lipids, or other sugars. When the sugar fucose is attached to a chain of sugars called glycans, they are said to be a fucosylated.
“Fucosylated glycans are critical in several cellular processes that affect development and immunity,” said study first author Dr. Yasuhiko Kizuka. “At the same time, defective fucosylation can lead to life threatening diseases.”
In this study, Kizuka and his team at RIKEN described how treatment with a modified fucose sugar can disrupt a biological pathway, which in turn prevents hepatoma—cancer cells in the liver—from becoming invasive.
Hepatoma are known to have excessive levels of fucosylated glycans. Thus, the RIKEN team reasoned that treatment targeting fucosylation in these cells might be effective in treating the cancer.
Biological pathways are chains of events in which a series of molecules interact with each other step by step, usually with the help of enzymes. In this case, several events transform glucose into a compound called GDP-fucose.
An enzyme then detaches fucose from GDP and joins it to a glycan. One way to inhibit this type of biological signaling process is to introduce molecular analogs—molecules that are similar to those needed in the chain of interactions.
The team at RIKEN used this strategy and compared the effects of two fucose analogs on fucosylation. Using several different types of cells, they found that one artificial sugar molecule, 6-alkynyl-fucose (6-Alk-Fuc), virtually abolished all cellular fucosylation.
The next step was to determine how fucosylation was blocked. Experiments showed that the analog did not prevent the transfer of fucose from GDP-fucose to glycans, indicating that fucosylation itself was not affected.
The team reasoned that the effect must occur earlier in the chain of events. Additional experiments showed that 6-Alk-Fuc blocked GDP-mannose from becoming GDP-fucose.
“The analog competed with GDP-mannose for attention from the enzyme GDP-L-fucose synthase, which prevented fucose from being made from GDP-fucose, making it impossible for downstream fucosylation to occur,” explained Kizuka.
With this knowledge in hand, they were able to test whether the 6-Alk-Fuc has the potential to treat liver cancer. Using several cell lines of hepatoma that had excessive levels of fucosylated glycans, they found that the analog was able prevent healthy extracellular matrix from being invaded by the hepatoma, also suppressing the migration of some hepatoma cell lines.
However, while 6-Alk-Fuc suppressed invasion, the treatment did not suppress hepatoma proliferation, meaning that the number of cancer cells continued to increase, even though they could not harm the healthy cells.
Kizuka noted that the invasion-suppressive property of this fucose analog makes it a potentially promising treatment for suppressing cancer metastasis in fucose-high cancers such as those found in the liver.
The article can be found at: Kizuka et al. (2017) An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3.
Source: RIKEN; Photo: Shutterstock.
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