BRL 49653 (rosiglitazone) is a thiazolidinedione anti-diabetic drug that activates the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). Pilot clinical trials have shown evidence of therapeutic activity of PPARgamma agonists against prostate cancer. To more effectively use PPARgamma ligands to treat this common and generally chemo-resistant type of cancer, it will be necessary to better understand the nature of PPARgamma activity in prostate cancer cells. Tumor suppressor effects of activation of PPARgamma 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. PPARgamma 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 beta-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 beta-catenin, which are regulated by PPARgamma 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 PPARgamma 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.
Copyright 2003 Wiley-Liss, Inc.