Sato Yuichiro, Matsubara Kiminori, Kubo Takanori, Sunayama Hirobumi, Hatori Yuta, Morimoto Kinjiro, Seyama Toshio
Department of Medical Pharmacy, Faculty of Pharmacy, Yasuda Women's University, Hiroshima 731-0153, Japan.
Department of Human Life Science Education, Graduate School of Education, Hiroshima University, Higashi-Hiroshima 739-8524, Japan.
Cancers (Basel). 2019 Apr 30;11(5):604. doi: 10.3390/cancers11050604.
lectin (PFL), which belongs to the high mannose (HM)-binding OAAH ( 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.
凝集素（PFL）属于高甘露糖（HM）结合型OAAH（凝集素同源物）凝集素家族，可诱导癌细胞死亡。然而，这一过程背后的详细机制尚未阐明。我们发现，PFL通过促进癌细胞中各种整合素以及表皮生长因子受体（EGFR）的内化和自噬降解，从而降低其表达水平，随后诱导半胱天冬酶 - 8依赖性细胞凋亡。正如使用大鼠主动脉模型进行的体外血管生成试验所显示的那样，PFL以剂量依赖性方式抑制新血管形成，这可能是由内皮整合素的下调介导的。有趣的是，PFL还下调癌细胞中的B7 - H4，B7 - H4被认为是T细胞介导免疫的负调节因子。我们发现，在MKN28胃癌细胞中，B7 - H4与β3整合素共定位。在MKN28细胞中对B7 - H4进行小干扰RNA（siRNA）沉默会降低β3整合素的表达，这表明这些分子之间存在物理和功能上的关联。通过表面等离子体共振分析检测PFL与整合素αvβ3或B7 - H4的直接相互作用，该分析检测到与PFL的高亲和力聚糖依赖性结合。这些研究表明，PFL与细胞表面整合素的相互作用是PFL抗癌活性的关键过程。
