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G-Protein Involvement in Matrix-mediated Motility and Invasion of High and Low Experimental Metastatic B16 Melanoma Clones¹

Dight Laboratories [B. R. L., Z. S., R. S. S.], University of Minnesota, Minneapolis, Minnesota 55455; Department of Laboratory Medicine and Pathology [B. R. L., J. B. M., Z. S., R. S. S., L. T. F.], University of Minnesota School of Medicine, Minneapolis, Minnesota 55455; and Branch Molecular Pathophysiology [A. M. S.], NIH, Bethesda, Maryland 20892

Membranes from a B16 murine melanoma clone of high experimental metastatic capacity show increased amounts of pertussis toxin (PT) substrate when compared to a low metastatic counterpart. Using specific antibodies, we identified G₁₂ as the PT-sensitive G-protein uniquely abundant in highly metastatic cells. ADP ribosylation of a G-protein subunit by PT decreased both the migration of tumor cells through Matrigel (Collaborative Research, Bedford, MA) and the fibronectin-, laminin-, and collagen type IV-mediated motility of a high metastatic clone. Treatment of cells from a low metastatic clone with PT did not alter either the relatively low invasive capacity or lower motility of these cells. While cholera toxin treatment of cells resulted in decreased invasion and motility of both high and low metastatic clones, there were significant qualitative and quantitative differences, when compared to the PT effects, which indicated that the two toxins were acting on different second messenger systems. PT treatment of B16 clones of high or low experimental metastatic capacity does not result in any alteration in cellular cyclic AMP accumulation suggesting that the PT substrate is not linked with the adenylyl cyclase enzyme complex. The data suggest that a PT-sensitive G-protein, possibly G₁₂, regulates second messenger pathways that contribute to the metastatic capacity of B16 melanoma cells.

¹ This work was supported by American Cancer Society Institutional Grant IN-13-Z-28 (B. R. L.); Minnesota Medical Foundation Grant CRF-113-88 (B. R. L.); National Cancer Institute/NIH Grant CA39510, CA43924 (J. B. M.) and CA21643, CA29995 (L. T. F.); and grants from the Leukemia Task Force, University of Minnesota (B. R. L., J. B. M., L. T. F.).

² To whom requests for reprints should be addressed at Dight Laboratories, University of Minnesota, 400 Church St., S. E., Minneapolis, MN 55455.

³ Recipient of the Allen-Pardee Professorship in Cancer Biology.

Received 2/ 2/89. Revised 4/17/89. Accepted 7/26/89.

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