Open Accessγ‐Tocotrienol inhibits ErbB3‐dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells
Author(s) -
Samant G. V.,
Sylvester P. W.
Publication year - 2006
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/j.1365-2184.2006.00412.x
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , erbb , erbb3 , receptor tyrosine kinase , tyrosine phosphorylation , signal transduction , biology , epidermal growth factor , phosphatidylinositol , phosphorylation , tocotrienol , cancer research , chemistry , microbiology and biotechnology , receptor , endocrinology , biochemistry , vitamin e , antioxidant , tocopherol
. The antiproliferative effects of γ‐tocotrienol are associated with suppression in epidermal growth factor (EGF)‐dependent phosphatidylinositol‐3‐kinase (PI3K)/PI3K‐dependent kinase‐1 (PDK‐1)/Akt mitogenic signalling in neoplastic mammary epithelial cells. Studies were conducted to investigate the direct effects of γ‐tocotrienol treatment on specific components within the PI3K/PDK‐1/Akt mitogenic pathway. +SA cells were grown in culture and maintained in serum‐free media containing 10 ng/ml EGF as a mitogen. Treatment with 0–8 µ m γ‐tocotrienol resulted in a dose‐responsive decrease in the +SA cell growth and a corresponding decrease in phospho‐Akt (active) levels. However, γ‐tocotrienol treatment had no direct inhibitory effect on Akt or PI3K enzymatic activity, suggesting that the inhibitory effects of γ‐tocotrienol occur upstream of PI3K, possibly at the level of the EGF‐receptor (ErbB1). Additional studies were conducted to determine the effects of γ‐tocotrienol on ErbB receptor activation. Results showed that γ‐tocotrienol treatment had little or no effect on ErbB1 or ErbB2 receptor tyrosine phosphorylation, a prerequisite for substrate interaction and signal transduction, but did cause a significant and progressive decrease in the ErbB3 tyrosine phosphorylation. Because ErbB1 or ErbB2 receptors form heterodimers with the ErbB3 receptor, and ErbB3 heterodimers have been shown to be the most potent activators of PI3K, these findings strongly suggest that the antiproliferative effects of γ‐tocotrienol in neoplastic +SA mouse mammary epithelial cells are mediated by a suppression in ErbB3‐receptor tyrosine phosphorylation and subsequent reduction in PI3K/PDK‐1/Akt mitogenic signalling.