A Sea Cucumber Sugar Blocks a Key Cancer Enzyme New

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Researchers found a potent cancer enzyme inhibitor in the sea cucumber Holothuria floridana.
Image credit:Vitor Pomin
Sea cucumbers feast on and clean up organic debris lying on the ocean floor, earning them the moniker “the janitors of the sea.” While many people also enjoy sea cucumbers as delicacies, few know that these humble organisms produce complex sugar molecules that may lead to promising cancer drugs.
Philip Gordts, a glycobiologist at the University of Utah, studies the role of proteoglycans in diseases.
Philip Gordts
Vitor Pomina glycobiologist at the University of Mississippi, and his colleagues previously showed that a sugar isolated from the sea cucumber Holothuria Floridana, called fucosylated chondroitin sulfate (HfFucCS), inhibits sulfatase-2 (Sulf-2), an enzyme involved in cancer cell invasion.1
Now, in a new study published in GlycobiologyPomin and his team found a unique structural motif in HfFucCS that is responsible for its potent inhibition.2 Their discovery could inform future efforts to synthesize small molecule inhibitors against Sulf-2.
“They used all the methods that are available in the field to understand how these inhibitors are working on a molecular level,” said Philip Gordtsa glycobiologist at the University of Utah who was not involved in the study.
Over the past two decades, medicinal chemists have tried to develop a potent inhibitor against Sulf-2, which is upregulated in various types of cancers.3 However, the synthesis of Sulf-2 inhibitors in the laboratory is both difficult and expensive. This drove Pomin to look to the natural world for molecules that mimic heparan sulfate, which binds Sulf-2.
Heparan sulfate is a glycosaminoglycan (GAG), which is a long sugar chain that decorates the extracellular side of many transmembrane proteins on the surface of cells. In the past, Pomin and his colleagues worked with multiple GAG analogs from marine organisms, including different species of sea urchins and sea cucumbers.4-10
“At first, we used the different GAG analogs to understand Sulf-2’s mechanism of action, not look for its inhibitor,” he said. “We found (HfFucCS) by accident, and I remember thinking, ‘Wow, this blocks Sulf-2 activity really, really well.’”
Vitor Pomin, a glycobiologist at the University of Mississippi, studies complex sugar molecules known as glycosaminoglycans in marine invertebrates.
Vitor Pomin
To investigate how well HfFucCS and other GAG analogs inhibit Sulf-2 activity, the team used a sulfatase activity assay developed in the laboratory of Radoslav Goldman of Georgetown University, a co-author of the study. The researchers found that among the tested molecules, HfFucCS was the most potent.
Because HfFucCS is a large and complex molecule, it can be difficult to synthesize in the laboratory and deliver therapeutically. So, Pomin and his colleagues wanted to identify the specific structural motif on HfFucCS that inhibits Sulf-2. Previously, the researchers had used depolymerization followed by size exclusion chromatography to generate fragments of HfFucCS.10 Using the same sulfatase activity assay, The researchers found that a HfFucCS fragment that is only 7.5 kDa in size, a mere 15 percent of its full molecular weight, can inhibit Sulf-2 as potently as the whole molecule.
Once they narrowed down the possible Sulf-2 binding sites on the HfFucCS fragment, the researchers performed computational molecular docking experiments to simulate the fraction’s interaction with Sulf-2. They identified a branched 3,4-disulfated fucose motif that is unique to HfFucCS and gave it its potency.
“The study was quantitative and rigorous,” said Steven Rosena glycobiologist and immunologist at the University of California, San Francisco, who was not involved in the study. “I’m very impressed and think very highly of it.”
However, Rosen cautioned that as a heparan sulfate mimetic, HfFucCS may have off-target effects that could lead to toxicity. Heparan sulfate interacts with a lot of molecules, including various growth factors and chemokines, so theoretically, HfFucCS could interact with them, too.
“They have not established that (HfFucCS) is a selective inhibitor,” Rosen said.
Steven Rosen, a glycobiologist and emeritus professor of anatomy at the University of California San Francisco, cloned Sulf-2 in mice and humans in the early 2000s.
Steven Rosen
Gordts added, “We don’t know how humans will react to the administration of these (marine invertebrate-derived) molecules.”
Pomin’s team previously showed that HfFucCS is minimally toxic in vitro, although Pomin acknowledged that these results were quite preliminary.10
Because environmental biologists are already concerned by the overharvesting of sea cucumbers for food, Pomin is currently collaborating with a medicinal chemist to find a way to synthesize the potent HfFucCS fraction in the laboratory. He also plans to assess HfFucCS’s potency and toxicity in animal models with Sulf-2 overexpression.
“(This study) established HfFucCS as a very potent inhibitor of Sulf-2, and that’s an accomplishment,” said Rosen.
- Mukherjee P, et al. Heparan-6-O-Endosulfatase 2 promotes invasiveness of head and neck squamous carcinoma cell lines in co-cultures with cancer-associated fibroblasts. Cancers (Basel). 2023;15(21):5168.
- Farrag M, et al. Heparan-6-O-endosulfatase 2, a cancer-related proteoglycan enzyme, is effectively inhibited by a specific sea cucumber fucosylated glycosaminoglycan. Glycobiology. 2025; 35 (6): CAF025.
- Rosen SD, Lemjabbar-Alaoui H. Sulf-2: An extracellular modulator of cell signaling and a cancer target candidate. Expert Opin Ther Targets. 2010;14(9):935-949.
- Kim SB, et al. Selective 2-desulfation of tetrasaccharide-repeating sulfated fucans during oligosaccharide production by mild acid hydrolysis. Carbohydr Polym. 2023;301(Pt A):120316.
- Chen S, et al. Sequence determination and anticoagulant and antithrombotic activities of a novel sulfated fucan isolated from the sea cucumber Isostichopus Badio. Biochim Biophys Acta. 2012;1820(7):989-1000.
- Pomin vh, et al. Selective cleavage and anticoagulant activity of a sulfated fucan: Stereospecific removal of a 2-sulfate ester from the polysaccharide by mild acid hydrolysis, preparation of oligosaccharides, and heparin cofactor II-dependent anticoagulant activity (published correction appears in Glycobiology. 2005 May;15(5):13G). Glycobiology. 2005;15(4):369-381.
- Shi X, et al. Structural characterization and heparanase inhibitory activity of fucosylated glycosaminoglycan from Holothuria Floridana. Mar Drugs. 2021;19(3):162.
- Shi D, et al. Comparison of hydrothermal depolymerization and oligosaccharide profile of fucoidan and fucosylated chondroitin sulfate from Holothuria Floridana. Int J Biol Macromol. 2019;132:738-747.
- Dwivedi R, et al. Structural and kinetic analyses of holothurian sulfated glycans suggest potential treatment for SARS-CoV-2 infection. J Biol Chem. 2021;297(4):101207.
- Farrag M, et al. Structural requirements of Holothuria Floridana fucosylated chondroitin sulfate oligosaccharides in anti-SARS-CoV-2 and anticoagulant activities. PLoS One. 2023; 18 (5): e0285539.