Fungal lectins show differential antiproliferative activity against cancer cell lines

Glycosylation patterns represent an important signature of cancer cells that can be decoded by glycan-binding proteins, i.e., lectins. Fungal lectins have unique properties and diverse structural and glycan-recognition features. In this study, the bioactivities of 22 fungal proteins against nine cancer cell lines were analyzed, and cell phenotypes were assessed with live cell imaging providing mechanistic insights. Eight fungal lectins showed antiproliferative activity, which depended on glycan binding and led to different downstream effects. The β-galactoside-binding chimerolectins Marasmius oreades agglutinin (MOA) and Laetiporus sulphureus lectin (LSL) showed indiscriminate antiproliferative activities with different modes of action, whereas the non-chimeric β-galactoside-binding lectin Agrocybe aegerita galectin (AAG) showed differential antiproliferative activity. Other β-galactoside-binding lectins exerted no effects. Fucose-binding lectins showed differential and strong antiproliferative activities, of which Aleuria aurantia lectin (AAL) exerted the strongest effects. Weaker anddifferential antiproliferative activities were observed with the Galβ1–3GalNAc-binding actinoporin-like lectins Xerocomus chrysenteron lectin (XCL), Sordaria macrospora transcript associated with perithecial development (TAP1), and Agaricus bisporus lectin (ABL). The different downstream effects of lectins, likely influenced by the targeted glycoligands, show that fungal lectins are valuable tools for identifying new therapeutic targets that can induce cancer cell death or growth arrest via different mechanisms. •Fungal lectins show differential antiproliferative activity on human cancer cell lines.•Different lectins have different antiproliferative mechanisms of action.•Glycan-binding is important but not sufficient for antiproliferative activity.•The bound glycoligands apparently influence the path to cell death or growth arrest.•Continuous live cell imaging and high-content analysis are valuable for drug discovery.