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

Yuichiro Sato,Kinjiro Morimoto,Yuta Hatori,Kiminori Matsubara,Hirobumi Sunayama,Takanori Kubo,Toshio Seyama

doi:10.3390/cancers11050604

Yuichiro Sato, Kinjiro Morimoto + Show 5 more

Open Access

https://doi.org/10.3390/cancers11050604

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Journal: Cancers	Publication Date: Apr 30, 2019
Citations: 5	License type: CC BY 4.0

Affiliation: Hiroshima University, Yasuda Women's University

Abstract

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.

Highlights

Integrins are heterodimeric glycoproteins that mediate cell adhesion to the extracellular matrix and immunoglobulin superfamily molecules
Our previous study demonstrated that the high mannose (HM) binding lectin Pseudomonas fluorescens lectin (PFL) directly bound to cell surface α2 integrins and epidermal growth factor receptor (EGFR), and promoted internalization of these molecules [12,14]
PFL decreased the level of α5 integrin in MKN28 cells, but α5 expression was not observed in HT29 cells

Summary

Introduction

Integrins are heterodimeric glycoproteins that mediate cell adhesion to the extracellular matrix and immunoglobulin superfamily molecules. Expressions of a wide variety of integrins, such as αvβ, αvβ, α5β1, and α6β4, on cancer cells have been reported to correlate with cancer progression, metastasis, and poor survival [1,2]. A growing body of evidence suggests that integrin crosstalk with growth factor receptors and cytokine. Depending on the cellular and environmental context, integrins form a molecular complex with growth factor receptors. Integrin β4 is physically associated with ErbB2 in breast cancer cells and thereby contributes to the growth and invasion of tumors [5]. It has been reported that integrin β5 forms a complex with epidermal growth factor receptor (EGFR) and contributes to pancreatic cancer metastasis [6]

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