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Effect of protein kinase C activating tumor promoters on metastases formation by fibrosarcoma cells.

The involvement of protein kinase C (PKC) in regulation of cellular properties related to tumor cell invasiveness was tested in a murine methylcholanthrene-induced fibrosarcoma tumor cell model. A metastatic clone (IE7) derived from the T10 fibrosarcoma was found to possess 30 and 90% more cytosolic and membrane-bound PKC, respectively, compared with the IC9 metastatic clone. Intravenous injection of IE7 but not IC9 cells resulted in lung tumor formation. Long-term (3 months) treatment of IE7 cells with 500 ng/ml phorbol 12,13-dibutyrate (PDB) resulted in a 4-fold reduction in total PKC activity and increase in the tumor cell metastatic ability. Short-term (2h) PDB treatment induced cytosol-to-membrane PKC translocation and decreased the IE7 cells' ability to form hematogenous metastases. Treatment of IC9 cells with PDB did not render them metastatic. To test the possible involvement of distinct PKC isoenzymes in the determination of metastatic properties, we stained the cells with appropriate anti-PKC antibodies followed by FACS analysis. IC9 and IE7 cells exhibited similar levels of fluorescent intensity when stained with either anti-PKC alpha or anti-PKC beta antibodies. The relative proportion of PKC alpha and PKC beta was not changed following short-term PDB treatment of cells, but the intensity of staining was reduced 1.5- to 2-fold following long-term PDB treatment of both cell types. The results indicate that phorbol ester-induced alterations in PKC levels and subcellular distribution affect the metastatic ability of tumor cells and suggest that tumor promoting agents that promote induction of primary tumors may also affect tumor spread by regulating hematogenous metastases formation.