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Biphasic Effects of 12-O-Tetradecanoylphorbol-13-acetate on the Cell Morphology of Low Calcium-grown Human Epidermal Carcinoma Cells: Involvement of Translocation and Down Regulation of Protein Kinase C¹

Department of Dermatology, Jichi Medical School, Minamikawachimachi, Kawachigun, Tochigi [Y. K., S. I., H. Y.], and Department of Biochemistry, Gifu University School of Medicine, Tsukasamachi, 40, Gifu [S. N., K. N., Y. N.], Japan

The present study was performed to investigate involvement of protein kinase C in the biphasic effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on cell morphology in low calcium (0.07 mM)-grown cells of a human epidermal squamous cell carcinoma cell line. The low calciumgrown cells formed no desmosomal cell-cell contact and showed roughly circular arrangements of keratin intermediate filaments around the nucleus. Treatment with 10 ng/ml of TPA induced a rapid formation (within 15 min) of cell-cell contact and reorganization of keratin intermediate filaments from a circular organization to a radial arrangement in these low calcium-grown cells. These structural phenomena were associated with a transient increase in membrane-bound protein kinase C activity. However, the prolonged treatment longer than 24 h led to a prominent decrease in the number of cell-cell contacts, that had been once formed, and caused fibroblastic changes of cell morphology in association with a decrease in the membrane-bound protein kinase C activity. Addition of 20 µM 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, a potential inhibitor of protein kinase C, to the medium with TPA blocked the formation of cell-cell contact. Addition of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride alone to normal calcium-grown cell cultures exhibiting cell-cell contact resulted in a decrease in the number of cell-cell contacts and in the fibroblastic morphological changes after 24-h incubation. These results suggest that the effects of TPA are biphasic as follows: the initial stage, inducing cell-cell contact formation associated with the translocation of protein kinase C activity from the cytosol to the membrane; and the late stage, exhibiting a fibroblastic morphological change with a decrease in the number of cell-cell contacts associated with the down regulation of this enzyme activity by TPA.

¹ This work was supported by a Grant in Aid for Scientific Research (B61480229) from the Ministry of Education, Science, and Culture of Japan.

² To whom requests for reprints should be addressed.

Received 4/ 9/87. Revised 8/31/87. Revised 10/30/87. Accepted 11/ 4/87.

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