Anticancer activity of Pseudomonas fluorescens lectin (PFL) targeting high-mannose glycans on breast cancer cells.

Aberrant glycosylation is one of the key characteristics of cancer cells. High-mannose-type N-glycans are highly expressed in various types of cancer, making them potentially important therapeutic targets. As a basis for developing new therapeutic drugs targeting high-mannose glycans, we employed Pseudomonas fluorescens lectin (PFL) that specifically binds to high-mannose glycans as a model compound, and analyzed the cellular responses of MDA-MB-231 and T47D breast cancer cell lines. In both cell types, PFL induced the internalization and degradation of cancer-associated molecules such as epidermal growth factor receptor (EGFR), integrins, and immune checkpoint ligands via autophagy, ultimately leading to apoptotic cell death. In T47D cells, changes were observed in the cellular distribution and expression levels of hormone receptors and human epidermal growth factor receptor 2 (HER2) upon treatment with PFL, suggesting a possible compensatory response. Comprehensive analysis of cellular lipids revealed that lysophospholipids were dramatically increased by PFL treatment, regardless of breast cancer cell type. These changes may reflect the dynamic reorganization of lipid membranes associated with membrane traffic and autophagy. Time-lapse experiments using a redox sensor designed to localize to the cell membrane showed that cells transitioned to an oxidized state following PFL treatment. Furthermore, inflammatory substances such as interleukin 8 (IL-8) were significantly increased in MDA-MB-231 cells but not in T47D cells. The results provide insight into the responses and resistance of breast cancer cells to glycan-targeted therapies.