PKCη is a negative regulator of AKT inhibiting the IGF-I induced proliferation

The PI3K-AKT pathway is frequently activated in human cancers, including breast cancer, and its activation appears to be critical for tumor maintenance. Some malignant cells are dependent on activated AKT for their survival; tumors exhibiting elevated AKT activity show sensitivity to its inhibition, providing an Achilles heel for their treatment. Here we show that the PKC eta isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKC eta-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKC eta-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on ART Ser473. While PKC eta exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERR phosphorylation. However, it enhanced ERK phosphorylation when stimulated by PDGF. Moreover, its effects on IGF-I/AKT and PDGF/ERK pathways were in correlation with cell proliferation. We further show that both PKC eta and IGF-I confer protection against UV-induced apoptosis and cell death having additive effects. Although the protective effect of IGF-I involved activation of AKT, it was not affected by PKC eta expression, suggesting that PKC eta acts through a different route to increase cell survival. Hence, our studies show that PKC eta provides negative control on AKT pathway leading to reduced cell proliferation, and further suggest that its presence/absence in breast cancer cells will affect cell death, which could be of therapeutic value. (C) 2012 Elsevier Inc. All rights reserved.