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Bidirectional Control of Membrane Expression and/or Activation of the Tumor Cell IRGpIIb/IIIa Receptor and Tumor Cell Adhesion by Lipoxygenase Products of Arachidonic Acid and Linoleic Acid¹

Departments of Radiation Oncology [I. M. G., L. A. U., K. K. N., J. D. T., K. V. H.], Biological Sciences [I. M. G., J. D. T., K. V. H.], Chemistry [K. V. H.], and Pathology [C. A. D.] Wayne State University, Detroit, Michigan 48202; Gershenson Radiation Oncology Center [J. D. T., K. V. H.] Harper/Grace Hospitals, Detroit, Michigan 48201; Gladstone Foundation Laboratories for Cardiovascular Disease [L. A. F.], and Department of Pathology [L. A. F.] University of California, San Francisco, California 94140-0608

Lewis lung carcinoma cells express a plasma membrane receptor (i.e., IRGpIIb/IIIa) which is immunologically and functionally related to the platelet aggregation receptor complex (i.e., GpIIb/IIIa). Both fluorescence microscopy and flow cytometric analysis reveal that surface expression and/or activation of this tumor cell receptor is enhanced by a phorbol ester [i.e., 12-O-tetradecanoylphorbol-13-acetate (TPA)] and a lipoxygenase metabolite of arachidonic acid; 12-hydroxyeicosatetraenoic acid (i.e., 12-HETE). TPA-enhanced expression appears to be mediated by a lipoxygenase metabolite, as this effect can be reversed by lipoxygenase inhibitors but not by cyclooxygenase inhibitors. In parallel with these results both TPA and 12(S)-HETE [but not 12(R)-HETE] enhance tumor cell adhesion to endothelial cells, subendothelial matrix and fibronectin, but not to type IV collagen. TPA-enhanced adhesion can be reduced by lipoxygenase inhibitors but not by cyclooxygenase inhibitors and in addition, stimulated adhesion can be blocked by pretreatment of tumor cells with specific polyclonal or monoclonal antibodies which react against IRGpIIb/IIIa. 12(S)-HETE-enhanced adhesion can also be inhibited by these same antibodies. In contrast, a lipoxygenase product of linoleic acid, 13(S)-hydroxyoctadecadienoic acid, inhibited TPA and 12(S)-HETE-enhanced tumor cell adhesion to endothelial cells, subendothelial matrix, and fibronectin. These results suggest that (a) IRGpIIb/IIIa is a multifunctional receptor which mediates tumor cell adhesion to a variety of biological substrata, (b) TPA enhances surface expression and/or activation of this receptor possibly via a lipoxygenase metabolite of arachidonic acid, and (c) these effects are opposed by a lipoxygenase metabolite of linoleic acid.

¹ This work was supported by USPHS Grants CA-29997 and CA-47115 awarded to K. V. Honn and a grant from Harper/Grace Hospitals.

² Irma M. Grossi is a predoctoral fellow on NIH training grant CA-09531-03.

³ Present Address: COR Therapeutics, 3330 Hillview Avenue, Palo Alto, CA 94304.

⁴ To whom requests for reprints should be addressed, at Wayne State University, Division of Cancer Biology, 431 Chemistry Building, Radiation Oncology Center, Detroit, MI 48202.

Received 7/ 7/88. Revised 11/ 7/88. Accepted 11/11/88.

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