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


RESULTS
Our current data show that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased beta1A-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 beta1A integrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-beta1A integrin, regulating PCa cell migration and invasion.


CONCLUSIONS
Our findings suggest that by a coordinated regulation of Cer levels, CathD and beta1A-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.
Stanley S Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Siyi
S
Hu
Nathalie
N
Delorme
Zhenzhen
Z
Liu
Tao
T
Liu
Cruz
C
Velasco-Gonzalez
Jone
J
Garai
Ashok
A
Pullikuth
Shahriar
S
Koochekpour
D001485:Basement Membrane / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002518:Ceramides / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000201:enzymology; D020868:Gene Silencing; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D049231:Saposins / Q000378:metabolism*
D002518:Ceramides; D019012:Integrin beta1; C483345:PSAP protein, human; D049231:Saposins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002402:Cathepsin D