P2-05-02: PGC1, Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) Coactivator-1, Is Necessary in PPAR-gamma Modulated Angiogenesis.

Abstract

Background. Peroxisome proliferator activated receptor- gamma (PPAR-gamma), a nuclear hormone receptor, has been shown to be an important regulator of gene expression. PPAR-gamma agonists have been shown to have anti-cancer properties by ways of inducing expression of tumour suppressor genes. It has been indicated that this action of PPAR-gamma is manifested by forming a complex with the PPAR-gamma coactivators (PGC1 &2) and in association with other transcription factors such as SRC-1 and CREB binding proteins. Both PPAR-gamma and PGC-1 have been shown to be aberrantly expressed in human cancer including human breast cancer (1). PPAR-gamma also plays a role in regulating angiogenesis and that PPAR-gamma agonists have been shown to have anti-angiogenic functions. In the present study, we investigated the role of PGC-1 in PPAR-gamma mediated actions on vascular endothelial cells. Materials and methods. Mammalian expression systems for human full length PGC-1 ereonstructed. Anti-PGC-1 transgenes were constructed again using human mammalian expression vector in order to knock down PGC-1 transcript from the cells. Human vascular endothelial cell, HECV, was used in the study. Cell functions linked to angiogenesis including cell adhesion and cellular migration was evaluated using the electric cell impedance sensing method. PPAR-gamma agonists and antagonists were used in the cell models during the analyses. Results. HECV cells weakly expressed PGC-1 and PPAR-gamma. Using the transgenes created, sublines over-expressing PGC1 (HECVPGC1exp) or with PGC-1 expression knockdown (HECVPGC1KD) were established. Loss of PGC1 showed marked increase in both adhesion and cellular migration, opposite was true forHECVPGC1exp cells. PPAR-gamma agonist, pioglitizone and ciglitizone, reduced the adhesion of control cells. In contrast, PPAR-gamma antagonist SR202 exhibited a concentration dependent stimulation of both adhesion and migration of the control cells. Knocking down PGC1 in endothelial cells rendered cells lost response to SR202. Conclusions. PGC-1 is essential in during the modulation of endothelial cells by PPAR-gamma. Together with the aberrant expression of both PPAR-gamma and PGC-1 in breast cancer, it is concluded that PGC-1 is a central player in PPAR-gamma mediated action in both cancer cells and angiogenesis. 1. Jiang WG, Douglas-Jones A, Mansel RE. Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. Int J Cancer. 2003, 106(5):752–757. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-02.