“Our findings offer new, unprecedented detail into the sugar’s role in cancer,” said Ze’ev Ronai, Ph.D., senior author and scientific director of SBP’s La Jolla campus. “We found that by tampering with L-fucose metabolism, we could inhibit melanoma tumor metastasis. Not only were the tumors affected but also their microenvironment—the cells surrounding the tumor that play a critical role in sustaining the cancer—making the discovery even more impactful.”
Sugars, such as glucose and sucrose, come from many different sources and are used by the body in unique ways. Some sugars, including L-fucose, provide crucial tags on cell-surface proteins that signal inflammation and help direct cell migration. Previous research has shown that changes in the amount of L-fucose on cells are associated with breast and stomach cancers.
The study started with a broader investigation of activating transcription factor 2 (ATF2), a protein that controls the expression of many other proteins and that has been implicated in the development of melanoma and other cancers. Ronai’s group has been studying ATF2 for more than 20 years.
"To our surprise, one of the genes found to be regulated by ATF2 was fucokinase (FUK), which controls the ability of cells to process the dietary sugar, L-fucose, into a form that is useable for the modification (fucosylation) of proteins, many of which are on the cell surface, said Ronai." “In human samples, we found reduced fucosylation in metastatic melanomas and a better prognosis for primary melanomas with increased fucosylation. We suspect that the absence of L-fucose on melanoma cells makes them less sticky and more mobile in the body, making them more likely to metastasize,” Ronai explained.
Importantly, in mice with melanoma, the researchers were able to increase fucosylation either by adding the sugar to their drinking water or by genetic manipulation. Both methods inhibited the growth and metastasis of the tumors.
“Many patients develop resistance to current melanoma drugs. If we can add something like L-fucose to enhance these therapies, that’s very exciting, and it’s something we’re actively looking into,” said lead author Eric Lau, Ph.D., who is extending studies on the role of L-fucose in melanoma at the H. Lee Moffitt Cancer Center in Tampa, Florida,
“The dietary result was especially gratifying, because it suggests that modifying fucosylation could be achieved by the simple addition of L-fucose to drinking water.
“Our results further suggest that the addition of dietary sugar may help fight melanoma by boosting numbers of helpful immune cells. We are continuing our exploration of how fucosylation and other sugar coatings affect the immune system and impact cancer,” added Ronai.
# # # This study was supported by NIH grant R01DK99551, NCI grant PO1 (CA128814),RO1 (CA179170), the Hervey Family Non-endowment Fund at the San Diego Foundation, the Melanoma Research Foundation, and K99 (CA172705) grantand T32 (CA121949) fellowship. This work was also supported by the AssistantSecretary of Defense for Health Affairs through the Peer-Reviewed Cancer Programunder Award No. W81XWH-14-1-0127.
About Sanford Burnham Prebys Medical Discovery InstituteSanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit research organization that blends cutting-edge fundamental research with robust drug discovery to address unmet clinical needs in the areas of cancer, neuroscience, immunity, and metabolic disorders. The Institute invests in talent, technology, and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs more than 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org. The Institute can also be found on Facebook at http://www.facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.
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