Abstract
ArtinM, a d-mannose-binding lectin from Artocarpus heterophyllus (jackfruit), interacts with N-glycosylated receptors on the surface of several cells of hematopoietic origin, triggering cell migration, degranulation, and cytokine release. Because malignant transformation is often associated with altered expression of cell surface glycans, we evaluated the interaction of ArtinM with human myelocytic leukemia cells and investigated cellular responses to lectin binding. The intensity of ArtinM binding varied across 3 leukemia cell lines: NB4>K562>U937. The binding, which was directly related to cell growth suppression, was inhibited in the presence of Manα1-3(Manα1-6)Manβ1, and was reverted in underglycosylated NB4 cells. ArtinM interaction with NB4 cells induced cell death (IC50 = 10 µg/mL), as indicated by cell surface exposure of phosphatidylserine and disruption of mitochondrial membrane potential unassociated with caspase activation or DNA fragmentation. Moreover, ArtinM treatment of NB4 cells strongly induced reactive oxygen species generation and autophagy, as indicated by the detection of acidic vesicular organelles in the treated cells. NB4 cell death was attributed to ArtinM recognition of the trimannosyl core of N-glycans containing a ß1,6-GlcNAc branch linked to α1,6-mannose. This modification correlated with higher levels of N-acetylglucosaminyltransferase V transcripts in NB4 cells than in K562 or U937 cells. Our results provide new insights into the potential of N-glycans containing a β1,6-GlcNAc branch linked to α1,6-mannose as a novel target for anti-leukemia treatment.
Highlights
Aberrant glycosylation of cell-surface glycoconjugates is a universal feature of cancer cells [1]
The fluorescence intensity in NB4 cells was at least 30% higher than in K562 and U937 cells, despite the ability of ArtinM lectin to bind more than 95% of cells in each cell line
Fluorescence microscopy confirmed ArtinM binding to NB4 cells (Fig. 1C); this binding was completely inhibited by pre-incubation with 10 mM Mana1-3[Mana1-6]Man, but not with 200 mM D-galactose, indicating that NB4 cell recognition by ArtinM is mediated by its carbohydrate recognition domain
Summary
Aberrant glycosylation of cell-surface glycoconjugates is a universal feature of cancer cells [1]. These alterations may be instrumental in the failure of intercellular contact and communication [2] and in the invasive and infiltrative properties of cancerous cells. The recognition of altered glycosylation in cancer cells by specific lectins has aided the assessment of cancer disease status [7,8]. Lectins can identify glycan determinants that are markers of clinical interest and may possess anti-tumor and anticarcinogenic properties that could be useful in the development of cancer therapeutics. Several studies have suggested that lectins can induce apoptosis in several human cancer cell lines [10,11,12]
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