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Autocrine Motility Factor Signals Integrin-mediated Metastatic Melanoma Cell Adhesion and Invasion¹

First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, H-1085, Hungary [J. Ti., J. To.]; Departments of Radiation Oncology [M. T., K. S., R. B., K. V. H.] and Pathology and Chemistry [K. V. H.], Wayne State University, Detroit, Michigan 48202; and Metastasis Research Program, Karmanos Cancer Institute, Detroit, Michigan 48201 [S. S., A. R.]

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 anti-body 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 IIbß3 and 5ß1 integrin receptors. In addition, AMF treatment of B16a cells increased translocation of IIbß3 and 5ß1 from the cytoplasm to the cell surface. However, IIbß3 and 5ß1 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 IIbß3 but not by antibodies to 5ß1. 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-lipoxygenase and protein kinase C.

¹ This work was supported by NIH Department of Health and Human Services Grants CA-47115-04 (to K. V. H.), CA-29997-08 (to K. V. H.), TW-285-02 (to K. V. H. and J. T.), and CA-51714 (to A. R.); The Paul Zuckermann Support for Cancer Research (to A. R.); NATO LG92311 (K. V. H. and J. T.); and the Hungarian National Science Fund, T6336 (to J. T.).

² The first two authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at Department of Pathology and Chemistry, 431 Chemistry. Wayne State University, Detroit, MI 48202. Phone: (313) 577-1018; Fax: (313) 577-0798.

Received 9/13/95. Accepted 2/15/96.

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