Endocrine Abstracts

It has been reported that Ang II induces the growth of MCF-7 breast cancer cells (Muscella et al., J Endocrinol 173, 315-323, 2002). Here we have examined the signalling pathways evoked by Ang II in MCF-7. Ang II did not change the concentration of intracellular calcium but induced the cytosol-to-membrane translocation of atypical protein kinase C zeta (PKC-zeta). Ang II dose-dependently induced c-fos (mRNA and protein) and enhanced the phosphorylation state of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). All these effects were blocked by the Ang II type I receptor (AT1) antagonist losartan but not by the AT2 antagonist CGP42112. High doses of the PKC inhibitor staurosporine (10 μM, which normally block atypical PKCs) abolished the Ang II-evoked c-fos induction and the phosphorylation of ERK1/2. The mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 suppressed the Ang II-evoked phosphorylation of ERK1/2 but not the induction of c-fos; moreover, the PI3K inhibitor wortmannin blocked the Ang II-induced phosphorylation of ERK1/2; wortmannin did not inhibit the activation of PKC-zeta nor the induction of c-fos. Finally, the inhibition of the epidermal growth factor-receptor (EGF-R) tyrosine kinase by AG1478 did not block the effect of Ang II on ERK1/2 phosphorylation. These findings suggest that in MCF-7 cells Ang II activates multiple signalling pathways involving PKC-zeta, and downstream the activation of PI3K and MAPK pathways. Of these activated pathways only PKC-zeta seems to be responsible for the Ang II-evoked c-fos induction.