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Activation of Microvascular Endothelium by Eicosanoid 12(S)-Hydroxyeicosatetraenoic Acid Leads to Enhanced Tumor Cell Adhesion via Up-regulation of Surface Expression of vβ3 Integrin: A Posttranscriptional, Protein Kinase C- and Cytoskeleton-dependent Process¹

Department of Radiation Oncology [D. G. T.; K. V. H.], Wayne State University, Harper Hospital, Detroit, Michigan 48202, Department of Pathology [C. A. D.; K. V. H.], Wayne State University, Harper Hospital, Detroit, Michigan 48202, Department of Chemistry [K. V. H.], Wayne State University, Harper Hospital, Detroit, Michigan 48202, Gershenson Radiation Oncology Center [K. V. H.], Harper Hospital, Detroit, Michigan 48202

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Wayne State University, 431 Chemistry, Detroit, MI 48202.

Tumor cell interaction with endothelial cells is a crucial step leading to organ-selective metastasis. Adhesion of murine B16 amelanotic melanoma cells (B16a) to murine microvascular endothelial cells (CD3) was enhanced, in a dose- and time-dependent manner, by pretreating CD3 cells with 12(S)-hydroperoxyeicosatetraenoic acid [i.e., 12(S)-HETE], a 12-lipoxygenase metabolite of arachidonic acid. The metabolic precursor of 12(S)-HETE, 12-HPETE (12-hydroperoxyeicosatetraenoic acid) also enhanced B16a cell adhesion to CD3 monolayers, whereas other lipoxygenase products, i.e., 5(S), 11(S), and 15(S)-HETEs were ineffective. 12(S)-HETE-enhanced tumor cell adhesion was blocked by treating endothelial cells with antibodies against the vβ3 complex or against individual sub-units but not with antibodies against 5β1. In contrast, neither of these two integrins appeared to be involved in tumor cell adhesion to unstimulated endothelium. Flow cytometric analysis, immunofluorescent labeling, and image analysis indicated that 12(S)-HETE induced a time- and dose-dependent increase in the surface expression of vβ3 but not 5β1 on CD3 cells. The increased surface expression of av/33 on endothelial cells did not result from an increased transcription or translation of βvβ3 message as confirmed by quantitative reverse transcription-polymerase chain reaction, Northern blotting, and quantitative Western blotting. Instead, subcellular fractionation studies revealed an increased translocation of βvβ3 integrins from the cytosolic pool to the membrane fractions. Pretreatment of endothelial cells with several cytoskeleton-disrupting agents (i.e., cycloheximide or acrylamide to disrupt intermediate filament vimentin, cytochalasin D to disrupt microfilaments, colchicine or Noco-dazole to disrupt microtubules) abolished the 12(S)-HETE-enhanced vβ3 surface expression as well as tumor cell adhesion to endothelial cells. Also, pretreatment of CD3 cells with protein kinase C inhibitor calphostin C, but not with protein kinase A inhibitor H8, blocked 12(S)-HETE-enhanced vβ3 surface expression and tumor cell adhesion. Collectively, these results suggest that eicosanoid 12(S)-HETE modulates tumor cell interaction with endothelium via protein kinase C- and cytoskeleton-dependent up-regulation of the surface expression of vβ3 integrin.

¹ Supported by NIH Grants CA-47115 and CA-29997 to K. V. H.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 2/93. Accepted 12/15/93.

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