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Protein Kinase C Involvement in Mammary Tumor Cell Metastasis¹

Adirondack Biomedical Research Institute, Lake Placid, New York 12946 [S. C. K., K. J. C., M. G., S. J.], and Jake Gittlen Cancer Research Institute (C7810), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [D. R. W., S. J.]

Metastasis requires cytoskeletal remodeling for migration, adhesion, and extravasation of metastatic cells. Although protein kinase C (PKC) is involved in tumor promotion/progression and cytoskeletal remodeling, its role in metastasis has not been defined. PKC levels are increased in highly metastatic 13762NF mammary tumor cells (MTLn3) compared with less metastatic, parental cell lines. To determine whether the increase in endogenous PKC is functionally related to their increased metastatic potential, we prepared MTLn3 cells that express the inhibitory regulatory domain fragment of PKC (RD) under the control of a tetracycline-inducible promoter. RD expression attenuated endogenous PKC activity, as demonstrated by decreased phosphorylation of the PKC substrate adducin in migrating cells. Thus, in MT cells, RD appears to primarily influence cytoskeleton-dependent processes rather than cell cycle progression. To determine whether RD expression influenced metastatic potential in vivo, MTLn3/RD cells were either grown in the mammary fat pad or injected into the tail vein of syngeneic rats, and effects of doxycycline-induced RD expression on pulmonary metastases were studied. Consistent with the in vitro data, induction of RD significantly reduced the number of lung metastases without affecting growth of the primary tumor. These results suggest that interfering with endogenous PKC activity by expressing the inhibitory RD fragment inhibits cytoskeleton-regulated processes important for MTLn3 cell metastasis.

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