Timar J, Trikha M, Szekeres K, Bazaz R, Tovari J, Silletti S, Raz A, Honn K V
First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary.
Cancer Res. 1996 Apr 15;56(8):1902-8.
The binding of autocrine motility factor (AMF) to its cell surface receptor, gp78, stimulates tumor cell motility. In this report, we provide evidence that stimulation of gp78 by either AMF or a monoclonal antibody to gp78 (3F3A) increases adhesion and spreading of metastatic murine melanoma (B16a) cells on fibronectin. This gp78-regulated increase is mediated by up-regulation of surface alphaIIbbeta3++ and alpha5beta1 integrin receptors. In addition, AMF treatment of B16a cells increased translocation of alphaIIbbeta3 and alpha5beta1 from the cytoplasm to the cell surface. However, alphaIIbbeta3 and alpha5beta1 demonstrate separate and unique staining patterns at the surface of B16a cells in response to stimulation of gp78. Furthermore, stimulation of B16a cells with AMF increased their invasion through Matrigel. This stimulated invasion was inhibited by antibodies to alphaIIbbeta3 but not by antibodies to alpha5beta1. The increased integrin surface expression and function in response to AMF was blocked by N-benzyl-N-hydroxy-5-phenylpentanamide, an inhibitor of 12-lipoxygenase, and calphostin C, an inhibitor of protein kinase C. The results demonstrate that AMF stimulates integrin-mediated B16a cell adhesion, spreading, and invasion, and these events are regulated by a signaling pathway involving 12-lipoxygenases and protein kinase C.
自分泌运动因子（AMF）与其细胞表面受体gp78的结合可刺激肿瘤细胞的运动。在本报告中，我们提供证据表明，AMF或抗gp78单克隆抗体（3F3A）对gp78的刺激可增加转移性小鼠黑色素瘤（B16a）细胞在纤连蛋白上的黏附与铺展。这种由gp78调节的增加是通过表面αIIbβ3和α5β1整合素受体的上调介导的。此外，用AMF处理B16a细胞可增加αIIbβ3和α5β1从细胞质向细胞表面的转运。然而，响应gp78的刺激，αIIbβ3和α5β1在B16a细胞表面呈现出不同且独特的染色模式。此外，用AMF刺激B16a细胞可增加其穿过基质胶的侵袭能力。这种刺激的侵袭受到抗αIIbβ3抗体的抑制，但不受抗α5β1抗体的抑制。12-脂氧合酶抑制剂N-苄基-N-羟基-5-苯基戊酰胺和蛋白激酶C抑制剂钙泊三醇可阻断AMF诱导的整合素表面表达增加和功能增强。结果表明，AMF刺激整合素介导的B16a细胞黏附、铺展和侵袭，且这些事件受涉及12-脂氧合酶和蛋白激酶C的信号通路调节。
