Matriptase/pdgf D/beta-Pdgfr Signaling Axis In Human Prostate Cancer: The Role Of Pten In The Regulation Of Pdgf D Expression

Platelet Derived Growth Factor (PDGF) is a family of mesenchymal growth factors that regulate cell proliferation, migration, and differentiation. Unlike the classic PDGF ligands A and B, which are secreted as active dimers, PDGF D must undergo extracellular proteolytic processing to remove its N-terminal CUB domain from the C-terminal PDGF growth domain before the ligand is able to stimulate its receptor, PDGF receptor beta (?-PDGFR). Importantly, recent clinical studies have shown that ?-PDGFR is upregulated in primary prostate cancer and bone metastases. However, PDGF B, formerly thought to be the sole ligand for ?-PDGFR, is not expressed in clinical prostate cancer samples. In a study of human primary prostate carcinoma and bone metastases, we found that PDGF D and matriptase are associated with prostate cancer progression. Additionally, in a clinically relevant prostate-specific PTEN (phosphatase and tensin homolog) knockout mouse model, we found an increase in PDGF D expression and ?-PDGFR phosphorylation upon loss of PTEN. Upon inhibition of the PI3K pathway, PDGF D/ ?-PDGFR induction was abolished in PTEN-/- cells. Among Akt isoforms, downstream effectors of PI3K, increased Akt3 expression was most prominent in PTEN-/- cells. These results suggest a molecular basis for activation of PDGF D/?-PDGFR signaling driven by the loss of PTEN, a frequent occurrence in human prostate cancer. Similarly, PTEN/Akt3 expression correlates with PDGF expression in human PCa cell lines, DU145 and PC3. Taken together, these results suggest that loss of PTEN in prostate cancer results in upregulation of PDGF D, which can then be activated by increased levels of serine proteases. The active growth domain is then able to activate ?-PDGFR, thus causing subsequent downstream signaling

PTEN Regulates PDGF Ligand Switch for β-PDGFR Signaling in Prostate Cancer

Platelet-derived growth factor (PDGF) family members are potent growth factors that regulate cell proliferation, migration, and transformation. Clinical studies have shown that both PDGF receptor β (β-PDGFR) and its ligand PDGF D are up-regulated in primary prostate cancers and bone metastases, whereas PDGF B, a classic ligand for β-PDGFR, is not frequently detected in clinical samples. In this study, we examined the role of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in the regulation of PDGF expression levels using both a prostate-specific, conditional PTEN-knockout mouse model and mouse prostate epithelial cell lines established from these mice. We found an increase in PDGF D and β-PDGFR expression levels in PTEN-null tumor cells, accompanied by a decrease in PDGF B expression. Among Akt isoforms, increased Akt3 expression was most prominent in mouse PTEN-null cells, and phosphatidylinositol 3-kinase/Akt activity was essential for the maintenance of increased PDGF D and β-PDGFR expression. In vitro deletion of PTEN resulted in a PDGF ligand switch from PDGF B to PDGF D in normal mouse prostate epithelial cells, further demonstrating that PTEN regulates this ligand switch. Similar associations between PTEN status and PDGF isoforms were noted in human prostate cancer cell lines. Taken together, these results suggest a mechanism by which loss of PTEN may promote prostate cancer progression via PDGF D/β-PDGFR signal transduction