Investigating the molecular and structural basis for the anti cancer cell adhesion properties of pectin galactans

Lead Research Organisation: Institute of Food Research
Department Name: Contracts

Abstract

Altered mucin 1 (MUC1) secretion/glycosylation patterns have been implicated in several cancerous conditions including gastric, colorectal and breast carcinomas. In particular, an association between the expression of MUC1, Thomsen-Friedenreich (TF) glycoantigen (Gal beta1–3GalNAc), and beta-galactoside-binding lectin galectin-3 (gal3) was recently reported to promote cancer cell adhesion to the endothelium. The involvement of galectins as pleiotropic regulators of cell adhesion and growth in disease progression explains the interest to define their ligand-binding properties. It has been proposed that pectic polysaccharides can act by binding to and inhibiting the various roles of the mammalian gal3 in cancer progression and metastasis and we have recently characterised galactan fragments binding to gal3. In the present study, we aim to investigate whether these pectin fragments can specifically disrupt the MUC1 TF antigen/gal3 interactions in vitro and in cell cultures. The project benefits from the complementary expertise in food carbohydrate biochemistry at the Institute of Food Research (IFR) and tumour cell-endothelial cell biology at the University of East Anglia (UEA). Combining experimental information from the binding data (in vitro and in cells) and X-ray crystal structures of galectin–carbohydrate ligand complexes derived from this "Pump priming grant" will enable the design of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer in the future. Natural carbohydrates have the advantage of being non-toxic therapies plus the long-term potential of protection in the diet.

Publications

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Leclaire C (2018) Molecular basis for intestinal mucin recognition by galectin-3 and C-type lectins. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

 
Description The work established a new collaboration between scientists from IFR and UEA to investigate the molecular mechanisms underlying the structure and function of circulatory galectin-3 (gal-3), a lectin implicated in tumour progression and metastasis. Modified citrus pectin, a complex indigestible polysaccharide obtained from the peel and pulp of citrus fruits is believed to act as an inhibitor of gal-3 activity but the interacting components and molecular basis of the interaction are unknown. We first set up an efficient expression system for the production of large amount of gal-3 to investigate (1) the effect of gal3 on tumour cells and (2) the interaction of pectin-derived components with gal-3. We showed that gal-3 markedly suppressed the expression of a key matrix metalloproteinase involved in tumour invasion. Structural and biochemical studies were performed to get more insights on the possible pectin-derived ligands that could inhibit gal-3 action. The methodology established during this pump priming grant was then used in a follow up investigating the interaction of Gal-3 with mucin (Leclaire et al., FASEB J. 2018).
Exploitation Route Our preliminary data suggest a novel and unforeseen mechanism by which gal-3 can promote cancer cell adhesion to the endothelium . As the potential and the necessity of developing pectin-based pharmaceuticals and nutraceuticals to counteract gal-3 action is becoming more and more commonly recognized, gaining basic knowledge on the molecular and structural requirement for interaction of specific galactan molecules to gal-3 is essential for the development of new antagonists and holds the promise of developing anti-cancer preventive and/or -therapeutic agents.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description This pump-priming grant provided a platform for carrying out detailed investigation on the role of pectins, and galectin-3 on tumour invasion. Aspects of the results from this grant have been presented at The British Society for Matrix Biology University of East Anglia, Norwich 6-7th September 2010 (Bevan D., Tolland J., Juge N., Gavrilovic J. (2010) Investigating alterations in tumour cell adhesion and protease expression in response to galectin-3. abstract published in International Journal of Experimental Pathology). This short grant allowed to set up the tools and collaborations to pursue the work further through joint master student projects between IFR and UEA.