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Published on: June 13, 2020
Structurally distinct enzymatic depolymerization products of Fucus evanescens fucoidan exert cell line-specific
Anastasiya O Zueva1, Artem S Silchenko1, Roman A Shkrabov1
1G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Laboratory of Enzyme Chemistry, 159 100-Let Vladivostoku Ave., 690022, Vladivostok, Russian Federation.
Abstract:
Fucoidans are sulfated polysaccharides from brown algae with promising anticancer properties, but the specific structural determinants underlying their biological effects remain poorly defined. Here, four different GH107 family endo-fucanases were used to depolymerize Fucus evanescens fucoidan (FeF), yielding eight high- (HMP) and low-molecular weight (LMP) derivatives differing Mw and sulfation. Enzymatic depolymerization revealed the hidden structure regularity of FeF fucoidan, characterized by extended mostly regular sites of [→4)-α-L-Fucp2S-(1→3)-α-L-Fucp2S-(1→]n and [→4)-α-L-Fucp2S-(1→3)-α-L-Fucp2,4S-(1→]n linked by less regular sites rich in 2,3-di-sulfated L-fucose residues. The ability of FeF and its enzymatic derivatives to inhibit the colony growth of human cancer cell lines (MCF-7, MDA-MB-231, DLD-1, HuTu80, and SK-MEL-28) was further tested. Reduction in FeF molecular weight (Mw) proved critical for inhibiting colony growth of DLD-1 and MCF-7 cells, with native FeF most potent and LMP derivatives showing practically no effect. In contrast, certain HMP or LMP derivatives with reduced Mw and optimized sulfate content and/or sulfation pattern (especially 2,4-di-sulfated) exhibited enhanced activity against MDA-MB-231, SK-MEL-28, and HuTu 80 cell lines compared to native FeF. Additional EGF-treatment was found to alter the sensitivity of certain cancer cells to specific structural motifs of fucoidans. Certain HMP and LMP derivatives also demonstrated enhanced chemopreventive effects against EGF-induced JB6 Cl41 transformation. These findings reveal that structural determinants of fucoidan anticancer effects differ not only by cancer cell type but also by exogenous or endogenous factors modulating cellular responses. These data further demonstrate the efficacy of specific endo-fucanases in tailoring native fucoidan structure to modulate its biological activity.
Insights
Fucoidan
Area of Science:
- Marine biotechnology and natural product chemistry.
- Carbohydrate chemistry and structural biology.
- Cancer research and chemoprevention.
Background:
- Fucoidans, sulfated polysaccharides from brown algae, show anticancer potential but their specific structural activity relationships are unclear.
- Understanding fucoidan structure is key to optimizing their therapeutic applications.
Purpose of the Study:
- To enzymatically depolymerize Fucus evanescens fucoidan (FeF) and characterize its derivatives.
- To evaluate the anticancer and chemopreventive activities of FeF derivatives against various cancer cell lines.
- To elucidate the structure-activity relationships of fucoidans in cancer therapy.
Main Methods:
- Enzymatic depolymerization of FeF using GH107 endo-fucanases to generate high- (HMP) and low-molecular weight (LMP) derivatives.
- Characterization of derivative structures, including molecular weight and sulfation patterns.
- In vitro assessment of antiproliferative activity against human cancer cell lines (MCF-7, MDA-MB-231, DLD-1, HuTu80, SK-MEL-28).
- Evaluation of chemopreventive effects against EGF-induced transformation in JB6 Cl41 cells.
Main Results:
- Enzymatic depolymerization revealed regular structural motifs within FeF, primarily composed of specific fucopyranose sulfate linkages.
- Native FeF was most potent against DLD-1 and MCF-7 cells, while its low-molecular weight derivatives showed reduced activity.
- Certain high- and low-molecular weight fucoidan derivatives with optimized sulfation (especially 2,4-di-sulfated) enhanced activity against MDA-MB-231, SK-MEL-28, and HuTu 80 cells.
- EGF-treatment modulated cancer cell sensitivity to fucoidan structural motifs.
- Specific fucoidan derivatives exhibited enhanced chemopreventive effects against EGF-induced transformation.
Conclusions:
- Fucoidan's anticancer effects are dependent on cancer cell type and modulated by factors like molecular weight, sulfation pattern, and cellular context.
- Enzymatic modification of fucoidans offers a strategy to tailor their structure and enhance their biological activity.
- Targeted structural modifications of fucoidans can lead to improved anticancer and chemopreventive agents.
