Plant Lectin Can Target Receptors Containing Sialic Acid, Exemplified by Podoplanin, to Inhibit Transformed Cell Growth and Migration

Abstract

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL) with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth.

Sialic Acids Sweeten a Tumor's Life

“…Current strategies include specific or global inhibition of sialyltransferases and other enzymes involved in sialic acid biosynthesis (e.g., GNE), overexpression and selective inhibition of sialidases, incorporation of unnatural (antigenic) sialic acid analogues into sialoglycans, and delivery of drugs to tumors using sialic acid-recognizing antibodies or newly developed phenylboronic acid-installed polymeric micelles (39)(40)(41)(42). Experimentally, some approaches have already produced promising results in vitro or in tumor mouse models.…”

Effects of selective cleavage of high-mannose-type glycans of Maackia amurensis leukoagglutinin on sialic acid-binding activity

“…The α2,3-sialic acid-binding lectin MAL is also used to recognize these carbohydrates in cancer cells [40]. It has recently been reported that orally administered MAL has potential in the treatment of malignant cancer characterized by a specific receptor [7]. Meanwhile, the present results indicate that the human cancer cell-binding activity of MAL was decreased by approximately 77% after the removal of high-Mantype N-linked glycans by PNGase F. It should therefore be necessary to maintain (or not cleave) these high-Man-type glycans on MAL in order to investigate the binding capacity of MAL to the surfaces of various cancer cells.…”

“…Plant N-linked glycans are classified as a high-mannose (Man)-type, with the structure of (Man) [5][6][7][8][9] N-acetylglucosamine (GlcNAc) 2 , a complex type, with a terminal GlcNAc or larger antennae that are β1,2-linked to the α1,6-or α1,3-Man of the core structure, and paucimannosidic-glycans, with an α1,3-fucose and/or a β1,2-xylose linked to the core pentasaccharide Man 3-2 GlcNAc 2 [15].…”

Src Points the Way to Biomarkers and Chemotherapeutic Targets

“…For example, kinase blockers, 67 siRNA, 67,82,134 antibodies, 67 and receptor blockers, including MASL (green), can target proteins involved in contact normalization to suppress cancer progression downstream of Src kinase activity. 166 …”

“…164,165 We have also found that specific lectins can target Pdpn to inhibit tumor cell growth and migration in vitro and in vivo. 166 …”