Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion

Abstract

BackgroundFactors responsible for invasive and metastatic progression of prostate cancer (PCa) remain largely unknown. Previously, we reported cloning of prosaposin (PSAP) and its genomic amplification and/or overexpression in several androgen-independent metastatic PCa cell lines and lymph node metastases. PSAP is the lysosomal precursor of saposins, which serve as activators for lysosomal hydrolases involved in the degradation of ceramide (Cer) and other sphingolipids.ResultsOur current data show that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased β1A-integrin expression, its cell-surface clustering, and adhesion to basement membrane proteins; led to disassembly of focal adhesion complex; and decreased phosphorylative activity of focal adhesion kinase and its downstream adaptor molecule, paxillin. Cathepsin D (CathD) expression and proteolytic activity, migration, and invasion were also significantly decreased in PSAP knock-down cells. Transient-transfection studies with β1A integrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-β1A integrin, regulating PCa cell migration and invasion.ConclusionOur findings suggest that by a coordinated regulation of Cer levels, CathD and β1A-integrin expression, and attenuation of "inside-out" integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy.

The MicroRNA-23b/27b/24 Cluster Promotes Breast Cancer Lung Metastasis by Targeting Metastasis-suppressive Gene Prosaposin

“…We have additionally uncovered the direct targeting of PSAP by miR-24 and miR-27b. PSAP, a highly conserved precursor for saposins A, B, C, and D, has been identified previously as a functional regulator of metastatic progression (36,37). Our results show that PSAP mRNA and protein expression is correlated with reduced metastatic potential and that ectopic PSAP expression is capable of inhibiting metastasis.…”

“…3C). PSAP is a secreted protein that has been described previously as both a metastasis promoter and suppressor (35)(36)(37). PSAP mRNA contained three predicted binding sites for the miR-23/27/24 clusters within the 3Ј-UTR, including two for miR-24 and one for miR-27 (Fig.…”

Sex-biased genetic effects on gene regulation in humans

“…S8) codes for a conserved glycoprotein involved in the development of the reproductive and nervous systems (Hu et al 2010). It has a developmental role in prostate cancer, its inactivation in mice leads to atrophy of the male reproductive system, and its downregulation decreases metastatic prostate cancer cell adhesion, migration, and invasion (Hu et al 2010). …”

Serum Glutamate Levels Correlate with Gleason Score and Glutamate Blockade Decreases Proliferation, Migration, and Invasion and Induces Apoptosis in Prostate Cancer Cells

“…Cell migration and invasion assays were performed using 8-μm transwell filters (Costar, Corning, NY) with the modifications described previously (25). For the invasion assay, the upper compartment was coated with 50 μg Matrigel (BD Biosciences, San Jose, CA) to form a matrix barrier.…”