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Possible Involvement of Ca²⁺ Mobilization and Protein Kinase C Activation in the Induction of Spontaneous Metastasis by Mouse Mammary Adenocarcinoma Cells¹

Division of Cancer and Cell Biology, Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada M5G 1X5 [B. K., C. W., R. S. K.], and Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada [R. S. K.]

Evidence is provided to show that two secondary cell-signaling pathways, Ca²⁺ mobilization and the activation of protein kinase C (PKC), are involved in the induction of spontaneous metastasis in mouse adenocarcinoma cell line SP1. Unlike the parental cells, which were found to be tumorigenic but unable to metastasize from a s.c. site, SP1 cells treated with ionophore A23187 (to mobilize Ca²⁺) or phorbol 12-myristate 13-acetate (to activate PKC) were able to metastasize spontaneously. Analysis of SP1 cells treated with either agent separately or with both agents simultaneously revealed that both pathways contributed to the final response in a separate and nonsynergistic way. The induced metastatic phenotype in most cases appeared to be heritable. Examination of Ca²⁺ sources during cell activation by ionophore A23187 suggested that internal Ca²⁺ was sufficient for the process of induction. Examination of PKC activity and its intracellular distribution during and after treatment of SP1 cells with ionophore A23187 and phorbol 12-myristate 13-acetate were also evaluated. The results suggested that the basal levels of PKC and the activation of the enzyme appear to be involved in the induction of spontaneous metastasis. Taken together, these observations are consistent with the hypothesis that cell-signaling pathways exist which can induce the metastatic phenotype and that this may be related to phosphatidylinositol turnover.

¹ This work was supported by grants from the National Cancer Institute of Canada, and the Medical Research Council of Canada (MT-5815) to R. S. K. R. S. K. is a Terry Fox Research Scientist of the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed, at Division of Cancer and Cell Biology, Mount Sinai Hospital Research Institute, 600 University Ave., Toronto, Ontario, Canada M5G 1X5.

Received 10/17/88. Revised 1/27/89. Accepted 2/10/89.

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