Carcinogenesis, Vol. 22, No. 2, 221-231,
February 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
Phosphorylation of connexin43 and inhibition of gap junctional communication in 12-O-tetradecanoylphorbol-13-acetate-exposed R6 fibroblasts: minor role of protein kinase CßI and µ
Department of Environmental and Occupational Cancer, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway
12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits gap junctional communication in many cell culture systems, but TPA-induced phosphorylation of the gap junction protein connexin43 (Cx43) varies much between systems. We have here studied whether these responses and their sensitivities can be correlated with total protein kinase C (PKC) enzyme activity and if specific PKC isoenzymes are involved. Rat R6 fibroblasts transfected with the cDNA sequence encoding PKCßI (R6-PKC3) had a total PKC activity 7- to 16-fold higher than the corresponding control cells (R6-C1), depending on the selection pressure (G418 concentration). Still, R6-PKC3 cells were no more sensitive than R6-C1 cells to TPA-induced down-regulation of communication, except at the highest selection pressure (500 µg/ml G418). Thus, total PKC activity does not indicate absolute sensitivity of a cell system to TPA-induced suppression of communication, but within a certain cell system increasing PKC activity may enhance the sensitivity to TPA in this respect. The results also suggest that PKCßI is of minor importance for TPA-induced regulation of communication. Experiments with the Lilly compound 379196, a PKCß-specific inhibitor, further supported this conclusion. Except for PKCßI in R6-PKC3 cells, both cell lines contained the TPA-responsive PKC isoenzymes 
, 
, 
and µ. Long-term treatment with TPA caused strong down-regulation of PKC, and , but little down-regulation of PKCµ. Concurrently, the cells became refractory to repeated exposure to TPA, indicating that PKCµ is of minor importance. Experiments with the general PKC inhibitor GF109203X and the PKC (and ß/
) inhibitor Gö6976 suggested that both classical () and novel PKCs ( and ) might be involved in TPA-induced suppression of intercellular communication, while phosphorylation of Cx43 may mainly be mediated by PKC in the present systems.
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