Gamma Tocopherol Upregulates the Expression of 15-S-HETE and Induces Growth Arrest Through a PPAR Gamma-Dependent Mechanism in PC-3 Human Prostate Cancer Cells

Abstract

Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that γ-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) γ, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that γ-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR γ mRNA and protein upregulation was achieved with γ-tocopherol within 6 h. γ-Tocopherol-mediated growth arrest was demonstrated to be PPAR γ dependent using the agonist GW9662 and a PPAR γ dominant negative vector. γ-tocopherol was shown not to be a direct PPAR γ ligand, but rather 15-S-HETE (an endogenous PPAR γ ligand) was upregulated by γ-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following γ-tocopherol treatment. Expression of proteins downstream of the PPAR γ pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFκ B proteins were found to be downregulated following γ-tocopherol treatment. These data demonstrate that the growth arrest mediated by γ-tocopherol follows a PPAR-γ-dependent mechanism.

ACKNOWLEDGMENTS

We would like to thank our grant sponsors for this work. Grant sponsors are American Institute for Cancer Research #05A119-REV2, Department of Defense Program Exploration and Hypothesis Development Award #PC030061, and Paul Dishner Chair of Excellence in Medicine, East Tennessee State of University. We would also like to thank Cognis Corporation, LaGrange, IL, for their generous supply of tocopherol. A special thanks to Dr. V. Krishna K. Chatterjee, Department of Medicine, University of Cambridge, Cambridge, UK, who has supplied us with the PPAR gamma dominant negative vector. I would like to acknowledge Dr. Lou Ernst-Fonberg for her advice, support, and technical assistance. I would like to thank the reviewers for their time and constructive comments.