Primary culture model of peroxisome proliferator‐activated receptor γ activity in prostate cancer cells

Abstract

BRL 49653 (rosiglitazone) is a thiazolidinedione anti-diabetic drug that activates the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARg). Pilot clinical trials have shown evidence of therapeutic activity of PPARg agonists against prostate cancer. To more effectively use PPARg ligands to treat this common and generally chemo-resistant type of cancer, it will be necessary to better understand the nature of PPARg activity in prostate cancer cells. Tumor suppressor effects of activation of PPARg may include suppression of growth and/or induction of differentiation or apoptosis. We investigated responses of primary cultures of human prostatic cancer cells to BRL 49653. PPARg was expressed in all of the cell strains examined. BRL 49653 caused dose-and time-dependent growth inhibition that was associated with increased expression of the transcription repressor, transforming growth factor b-stimulated clone 22 (TSC-22), and markedly increased expression of the secretory differentiation-associated gene adipophilin. Adipocyte-type fatty acid binding protein (aFABP), neutrophil gelatinase-associated lipocalin (NGAL), glycerol kinase (GyK), and b-catenin, which are regulated by PPARg ligands in certain other types of cells, were not regulated by BRL 49653 in prostate cells. Upregulation of adipophilin coincided with morphological changes and the appearance of cytoplasmic vacuoles with ultrastructural features of secondary lysosomes. These results extend previous studies with established cancer cell lines and show that PPARg agonists can inhibit proliferation and modulate expression of secretory-associated genes in primary cultures of prostate cancer cells, further warranting consideration of these agents as pro-differentiating chemotherapeutic or chemoprevention agents for the treatment of prostate cancer.

Inhibitory effect of microRNA-24 on fatty acid-binding protein expression on 3T3-L1 adipocyte differentiation

“…To our knowledge, our study is the first to report an inhibitory effect of miR-21 on FABP4. FABP4 is expressed mainly in adipocytes and macrophages (Xu et al, 2003). Its expression and activity increase during adipocyte differentiation and promote adipocyte differentiation.…”

A role for GATA-2 in transition to an aggressive phenotype in prostate cancer through modulation of key androgen-regulated genes

“…During pre-adipocyte to adipocyte transition induced by peroxisome proliferator-activated receptor-gamma (PPAR-g) agonists, levels of GATA-2 are reduced with a concomitant increase in the levels of AZGP1 and PPAR-g (Tong et al, 2000;Bao et al, 2005). The pro-differentiating effects of PPAR-g agonists in primary prostate cells and cell lines are well documented (Xu et al, 2003). However, the mechanism by which PPAR-g induces differentiation in these cells is unknown (Matsuyama and Yoshimura, 2008).…”

Primary cell cultures as models of prostate cancer development

“…Agonists of PPARg have shown some clinical activity in pilot studies on prostate cancer (Koeffler 2003). Treatment of normal prostatic epithelial cells with the PPARg agonist, rosiglitazone, resulted in growth suppression and induction of a unique phenotype whose characteristics remain to be more fully elucidated (Xu et al 2003).…”