%0 Journal Article
%T Mechanisms Mediating the Effects of ¦Ă-Tocotrienol When Used in Combination with PPAR¦Ă Agonists or Antagonists on MCF-7 and MDA-MB-231 Breast Cancer Cells
%A Abhita Malaviya
%A Paul W. Sylvester
%J International Journal of Breast Cancer
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/101705
%X ¦Ă-Tocotrienol is a natural vitamin E that displays potent anticancer activity, and previous studies suggest that these effects involve alterations in PPAR¦Ă activity. Treatment with 0.5¨C6Łż¦ĚMŁżŁż¦Ă-tocotrienol, 0.4¨C50Łż¦ĚM PPAR¦Ă agonists (rosiglitazone or troglitazone), or 0.4¨C25Łż¦ĚM PPAR¦Ă antagonists (GW9662 or T0070907) alone resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 breast cancer proliferation. However, combined treatment of 1¨C4Łż¦ĚMŁżŁż¦Ă-tocotrienol with PPAR¦Ă agonists reversed the growth inhibitory effects of ¦Ă-tocotrienol, whereas combined treatment of 1¨C4Łż¦ĚMŁżŁż¦Ă-tocotrienol with PPAR¦Ă antagonists synergistically inhibited MCF-7 and MDA-MB-231 cell growth. Combined treatment of ¦Ă-tocotrienol and PPAR¦Ă agonists caused an increase in transcription activity of PPAR¦Ă along with increased expression of PPAR¦Ă and RXR, and decrease in PPAR¦Ă coactivators, CBP p/300, CBP C-20, and SRC-1, in both breast cancer cell lines. In contrast, combined treatment of ¦Ă-tocotrienol with PPAR¦Ă antagonists resulted in a decrease in transcription activity of PPAR¦Ă, along with decreased expression of PPAR¦Ă and RXR, increase in PPAR¦Ă coactivators, and corresponding decrease in PI3K/Akt mitogenic signaling in these cells. These findings suggest that elevations in PPAR¦Ă are correlated with increased breast cancer growth and survival, and treatment that decreases PPAR¦Ă expression may provide benefit in the treatment of breast cancer. 1. Introduction Peroxisome proliferator activated receptor ¦Ă (PPAR¦Ă) belongs to the nuclear receptor superfamily and functions as a ligand-activated transcription factor that forms a heterodimer complex with retinoid X receptor (RXR). This complex then binds to a specific DNA sequence called the peroxisome proliferator response element and initiates the recruitment of coactivator proteins such as CBP p/300, SRC-1, and CBP C-20, which further modulate gene transcription [1¨C3]. Studies have shown that PPAR¦Ă is overexpressed in many types of breast cancer cells [4¨C7]. Experimental evidence in rodents has shown that overexpression of PPAR¦Ă is associated with an increased incidence and growth in mammary tumors, whereas knockdown of PPAR¦Ă expression was found to significantly inhibit spontaneous mammary tumor development [8, 9]. Taken together these results suggest that inhibition of PPAR¦Ă expression and/or activity may be beneficial in the treatment of breast cancer. However, other studies have shown that treatment with the PPAR¦Ă agonist rosiglitazone and troglitazone, or conversely with PPAR¦Ă antagonists GW9662 and T0070907, were both found
%U http://www.hindawi.com/journals/ijbc/2013/101705/