Tumor promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis.
A strong correlation was found between the basal levels of membrane-bound protein kinase C and the ability of B16 melanoma cell sublines (F10, F1, and BL6) to metastasize to the lung after intravenous injection. By treating with tumor-promoting phorbol esters for 1 hr, the low-metastasizing F1 cells exhibited both translocation of protein kinase C from cytosol to plasma membrane and an increase in metastasis to a level comparable to the (untreated) highly metastatic subline F10. Prolonged treatment of melanoma sublines with phorbol 12-myristate 13-acetate for 24 hr resulted in both inactivation of protein kinase C activity and loss of their metastasizing capabilities. Under conditions that induced only the activation of protein kinase C but not its membrane association, no increase in metastasis occurred, suggesting that activation of protein kinase C alone is insufficient to promote metastasis and that its membrane association is also necessary. Exposure of B16 melanoma sublines to phorbol esters for 1 hr had (i) no effect on the growth and morphology of these cells in vivo and in vitro and (ii) a short-term effect (approximately equal to 5 hr) on membrane association of protein kinase C. Nonetheless, in this period, the membrane-bound protein kinase C, probably by influencing cell-surface and cell-attachment properties, increased the retention of circulating melanoma cells in the lung, which eventually led to an increased number of metastatic nodules. The membrane-bound protein kinase C activity also correlated with metastatic ability in rapidly growing cells, growth-arrested cells, and cells growing in a low-Ca2+ medium. The results strongly suggest that the membrane-bound protein kinase C influences hematogenous metastasis of tumor cells and show that tumor promoters like phorbol esters have an additional role in promoting hematogenous spread of cancer in the body.
Department of Pathology, School of Medicine, University of California, Los Angeles 90024.
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Gopalakrishna
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Barsky
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004790:Enzyme Induction; D007700:Kinetics; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology*; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D002273:Carcinogens; D010703:Phorbol Esters; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate