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Atypical PKC‐ζ and PKC‐ι mediate opposing effects on MCF‐7 Na+/K+ATPase activity

We demonstrated previously that in serum‐starved MCF‐7 breast cancer cell line, Ang II increased Na+/K+ATPase activity and activated the protein kinase C ζ (PKC‐ζ) (Muscella et al., 2002 J Endocrinol 173:315–323; 2003 J Cell Physiol 197:61–68.). The aim of the present study was to investigate the modulation of the activity of the Na+/K+ATPase by PKC‐ζ in MCF‐7 cells. Here, using serum‐starved MCF‐7 cells, we have demonstrated that the effect of Ang II on the Na+/K+ATPase activity was inhibited by a synthetic myristoylated peptide with sequences based on the endogenous PKC‐ζ pseudosubstrate region (ζ‐PS) and by high doses of GF109203X, inhibitor of PKCs. When MCF‐7 cells, grown in 10% fetal bovine serum (FBS), were stimulated with Ang II a dose‐ and time‐dependent inhibition of the Na+/K+ATPase activity was obtained. Under this growth condition we found that mRNAs for AT1, AT2, and for Na+/K+ATPase α1 and α3 subunits were unchanged; besides both the activity of the Na+/K+ATPase and the level of PKC‐ζ also were unaffected by the serum. The atypical PKC‐ι level (present in very low abundance in serum‐starved MCF‐7) was increased and Ang II provoked its translocation from the cytosol to plasma membrane. PKC‐ζ was localized to the membrane, and upon Ang II treatment its cellular localization did not change. The Ang II‐mediated decrease of the Na+/K+ATPase activity was inhibited by high doses of GF109203X but not by ζ‐PS, thus indicating that such effect was not due to PKC‐ζ activity. The treatment of cells with PKC‐ι antisense oligodeoxynucleotides inhibited the effects of Ang II on the Na+/K+ATPase activity. Additionally, the effect of Ang II on Na+/K+ATPase activity was also blocked by the phosphatidylinositol 3‐kinase (PI3K) inhibitors, wortmannin and LY294002, and by the actin depolymerizing agents, cytochalasin D. In conclusion, in MCF‐7 cells Ang II modulates the Na+/K+ATPase activity by both atypical PKC‐ζ/‐ι. The effects of Ang II are opposite depending upon the presence of the serum‐sensitive PKC‐ι, with the inhibitory effect possibly due to the redistribution of sodium pump from plasma membrane to the inactive intracellular pool. © 2005 Wiley‐Liss, Inc.