High Mannose Binding Lectin (PFL) from Pseudomonas fluorescens Down-Regulates Cancer-Associated Integrins and Immune Checkpoint Ligand B7-H4

Cancers

Kiminori Matsubara¹  Takanori Kubo²  Yuta Hatori²  Toshio Seyama²  Yuichiro Sato³  Kinjiro Morimoto³  Hirobumi Sunayama⁴ 

[1] Department of Human Life Science Education, Graduate School of Education, Hiroshima University, Higashi-Hiroshima 739-8524, Japan;Department of Life Sciences, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima 731-0153, Japan;Department of Medical Pharmacy, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima 731-0153, Japan;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima 731-0153, Japan;

关键词: lectin;    integrin;    autophagy;    angiogenesis;    immune checkpoint;   

DOI  :  10.3390/cancers11050604

来源: DOAJ

【 摘 要 】

Pseudomonas fluorescens lectin (PFL), which belongs to the high mannose (HM)-binding OAAH (Oscillatoria agardhii agglutinin homologue) lectin family, induces cancer cell death. However, the detailed mechanisms underlying this process have not yet been elucidated. We found that PFL decreased various integrins as well as EGFR in cancer cells by promoting internalization and autophagic degradation of these molecules, subsequently inducing caspase-8 dependent cell apoptosis. As revealed by an ex vivo angiogenesis assay using the rat aortic model, PFL inhibited neovascularization in a dose-dependent manner, which was potentially mediated by down-regulation of endothelium integrins. Interestingly, PFL also down-regulated B7-H4 in cancer cells, which has been implicated as a negative regulator of T cell-mediated immunity. We found that B7-H4 co-localized with β3 integrin in MKN28 gastric cancer cells. siRNA silencing of B7-H4 in MKN28 cells decreased expression of β3 integrin, suggesting physical and functional association between these molecules. Direct interaction of PFL with integrin αvβ3 or B7-H4 was examined by surface plasmon resonance analysis, which detected high affinity glycan-dependent binding to PFL. These investigations suggest that PFL interaction with cell surface integrins is a key process for the anti-cancer activities of PFL.

【 授权许可】

Unknown