ABSTRACT
Recent studies suggest that glypican-1 (GPC-1) is a biomarker for prostate cancer, but there are few studies elucidating the role of GPC-1 in prostate cancer progression. We observed high expression of GPC-1 in more aggressive prostate cancer cell lines such as PC-3 and DU-145. While inhibition of GPC-1 expression in PC-3 cells decreased cell growth and migration in vitro, it surprisingly increased cell proliferation and migration in DU-145 cells, suggesting that the role of GPC-1 is cell type-dependent. Further, GPC-1 inhibition increased PC-3 tumor size in NCr nude mice xenografts. We hypothesized that the discrepancy between the in vitro and in vivo data is mediated by stromal cells in the tumor microenvironment. Thus, we tested the effect of tumor conditioned media (TCM) on gene expression in human mesenchymal stem cells and fibroblasts. Treatment of stromal cells with TCM from PC-3 cells transfected with GPC-1 shRNA increased the expression of migration markers, endocrine/paracrine biomolecules, and extracellular matrix components. Additionally, the decreased cell growth in GPC-1 knockdown PC-3 cells was rescued by coculturing with stromal cells. These data demonstrate the paradoxical role that GPC-1 plays in prostate cancer cell growth by interacting with stromal cells and through ECM remodeling and endocrine/paracrine signaling.
Subject(s)
Antineoplastic Agents/pharmacology , Extracellular Matrix/pathology , Glypicans/metabolism , Prostatic Neoplasms/pathology , Stromal Cells/pathology , Animals , Antineoplastic Agents/therapeutic use , Cell Culture Techniques , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Coculture Techniques , Culture Media, Conditioned , Extracellular Matrix/drug effects , Fibroblasts , Gene Knockdown Techniques , Glypicans/antagonists & inhibitors , Glypicans/genetics , Humans , Male , Mesenchymal Stem Cells , Mice , Paracrine Communication/drug effects , Prostate/cytology , Prostate/pathology , Prostatic Neoplasms/drug therapy , Stromal Cells/drug effects , Tumor Burden/drug effects , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Extensive evidence suggests that decline in ovarian function with menopause is associated with neuronal dysfunction. Major cause of this is rise in oxidative stress and inflammatory cytokines because of estrogen deficiency. 17ß-Estradiol (E2, hormone with potent antioxidant and anti-inflammatory activity) has profound protective actions on multiple organ systems, but feminizing side effects of ß-estradiol limits its clinical efficacy. 17α-Estradiol (E2α), a non feminizing congener, gives a ray of hope to the scientific community as an alternative strategy to treat menopause associated neuronal pathologies. We assessed the protective actions of 17α-estradiol (5, 10µg/kg) against cognitive deficits, depression and motor coordination after 4weeks of ovariectomy in rats and compared its efficacy with E2 at same doses. After the behavioral assay animals were sacrificed and their brains were harvested for biochemical studies. Uterine weights were also assessed. E2 and E2α (5, 10µg/kg) were equally protective against attenuating cognitive deficits, depressive symptoms and motor incoordination in OVX rats. Both demonstrated significant antioxidant activity and E2, but not E2α, increased serum estradiol levels and proliferated uterine weights, markers of feminizing action. It can thus be concluded that E2α offers safe alternative to E2 in protecting against menopausal neuropathologies.
