Le. Roseng et E. Rivedal, TPA INHIBITION OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN SYRIAN-HAMSTER EMBRYO CELLS THROUGH 2 DIFFERENT PATHWAYS, Toxicology in vitro, 7(5), 1993, pp. 631-636
Exposure of early passage Syrian hamster embryo cells to high TPA conc
entrations (8 or 16 mu M) decreased gap junctional intercellular commu
nication (GJIC) to about 20% of the control during the first hour. Sub
sequently, the GJIC capacity recovered to 70-80% after 4-10 hr. Exposu
re to lower TPA concentrations also reduced GJIC, but did not result i
n the subsequent rapid enhancement of communication. Treatment of the
cells to different TPA concentrations down-regulated protein kinase C
(PKC), but this down-regulation did not seem to explain fully the indu
ced recurrence of GJIC following high TPA concentrations. The maximal
down-regulation of PKC took place at TPA concentrations above 0.16 mu
M. Addition of 8 mu M TPA to cells pretreated with 0.016 and 8 mu M fo
r 10 hr reduced GJIC from 80 to 40%, whereas pretreatment with 0.16 or
1.6 mu M TPA made the cells refractory to further TPA-induced inhibit
ion. The PKC inhibitor staurosporine suppressed the effect of TPA on G
JIC in cells exposed to 0.016 mu M TPA, whereas no suppression was obs
erved in cells depleted of PKC. The results indicate that TPA is capab
le of inhibiting GJIC through two different mechanisms, a staurosporin
e-sensitive mechanism at low TPA concentrations (EC(50) = 0.18 mu M) a
nd a staurosporine-insensitive mechanism at higher concentrations (EC(
50) = 7 mu M).