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

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• 作者：Galit Shahaf¹ ; Noa Rotem-Dai¹ ; Gabriela Koifman ; Hadas Raveh-Amit ; Sigal A. Frost ; Etta Livneh ; ^{etta@bgu.ac.il}
• 关键词：PKB ; protein kinase B ; PKC ; protein kinase C ; PMA ; phorbol 12-myristate 13-acetate ; IGF ; Insulin-like growth factor ; PDGF ; platelet derived growth factor ; PDK-1 ; Phosphoinositide-dependent kinase-1 ; PI3K ; phosphatidylinositol 3-kinase ; shRNA ; short hairpi
• 刊名：Experimental Cell Research
• 出版年：2012
• 期刊代码：292_00144827
• 类别：med
• 出版时间：15 April, 2012
• 卷：318
• 期：7
• 页码：789-799
• 文件大小：912 K

摘要

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畏 isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKC畏-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKC畏-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on AKT Ser473. While PKC畏 exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERK 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畏 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畏 expression, suggesting that PKC畏 acts through a different route to increase cell survival. Hence, our studies show that PKC畏 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.