Abstract 150: Combined treatment effects of γ-tocotrienol with PPARγ agonists and antagonists on MCF-7 and MDA-MB-231 breast cancer cell growth in culture

Abstract

γ-Tocotrienol (γT3) is a member of the vitamin E family of compounds that displays potent antiproliferative effects against breast cancer cells. Recent studies have shown that combined treatment of subeffective doses of γ-T3 with subeffective doses of statins, cyclooxygenase-2 inhibitors, or EGF receptor inhibitors caused a synergistic inhibition in the highly malignant +SA mammary epithelial cell growth. Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor family is a ligand activated transcription factor that directly regulates transcription of target genes. The present study investigated the effects of γT3 used in combination with PPARγ agonists and antagonists on breast cancer cell growth in culture. Treatment with 0.5-6μM γT3, 0.4-50μM PPARγ agonist (rosiglitazone or troglitazone) or 0.4-25 PPARγ antagonist (GW9662 or T0070907) alone resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 breast cancer cell growth. However, combined treatment with subeffective doses (2-3μM) of γT3 with subeffective doses (3-5μM) or PPARγ agonists was found to increase MCF-7 and MDA-MB-231 cell growth, whereas combined treatment with similar subeffective doses of γT3 with subeffective doses (4-6μM) of PPARγ antagonists was found to significantly inhibited growth of both breast cancer cell lines. Western blot analysis showed that combined treatment with similar subeffective doses of γT3 and PPARγ antagonists resulted in a relatively large decrease in the levels of phosphorylated PPARγ and its heterodimer partner, retinoid X receptor (RXR), in a time-dependent manner. In addition, combined treatment with these agents caused an overexpression of specific PPARγ transcriptional co-activators including, CREB-binding protein H-300 (CBP H-300), CBP C-20, and steroid receptor co-activator-1 (SRC-1). These results indicate that the anti-proliferative effects induced by combined treatment of γT3 with PPARγ antagonists are mediated through a PPARγ-dependent mechanism in these breast cancer cell lines. Additional studies showed that the antiproliferative effects induced by combined treatment with γT3 and PPARγ antagonists was also associated with a reduction in phosphatidylinositol-3-kinase (PI3K)/PI3-K-dependent kinase (PDK)/Akt mitogenic signaling in MCF-7 and MDA-MB-231 human breast cancer cell lines. In summary, these findings strongly suggest that the antiproliferative effects of combined treatment of γT3 and PPARγ antagonists in breast cancer cells are mediated by suppression in PPARγ-RXR phosphorylation and subsequent reduction in PI3K/PDK/Akt mitogenic signaling. This study was supported by a grant from First Tech International Ltd., and the Malaysian Palm Oil Council. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 150. doi:1538-7445.AM2012-150