Synergistic Antiproliferative Effects of Combinedγ-Tocotrienol and PPARγAntagonist Treatment Are Mediated through PPARγ-Independent Mechanisms in Breast Cancer Cells

Abstract

Previous findings showed that the anticancer effects of combinedγ-tocotrienol and peroxisome proliferator activated receptorγ(PPARγ) antagonist treatment caused a large reduction in PPARγexpression. However, other studies suggest that the antiproliferative effects ofγ-tocotrienol and/or PPARγantagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγin mediating the effects of combined treatment ofγ-tocotrienol with PPARγagonists or antagonists on the growth of PPARγnegative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment ofγ-tocotrienol with PPARγantagonist decreased, while combined treatment ofγ-tocotrienol with PPARγagonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combinedγ-tocotrienol and PPARγantagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2(PGD2) synthesis. In conclusion, the anticancer effects of combinedγ-tocotrienol and PPARγantagonists treatment in PPARγnegative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2synthesis.