Differential tumorigenic potential and matriptase activation between PDGF B versus PDGF D in prostate cancer.

Abstract

The platelet-derived growth factors (PDGF A, B, C, and D) and their receptors (α-PDGFR and β-PDGFR) play an indispensible role in physiologic and pathologic conditions, including tumorigenesis. The transformative β-PDGFR is overexpressed and activated during prostate cancer progression, but the identification and functional significance of its complementary ligand have not been elucidated. This study examined potential oncogenic functions of β-PDGFR ligands PDGF B and PDGF D, using nonmalignant prostate epithelial cells engineered to overexpress these ligands. In our models, PDGF D induced cell migration and invasion more effectively than PDGF B in vitro. Importantly, PDGF D supported prostate epithelial cell tumorigenesis in vivo and showed increased tumor angiogenesis compared with PDGF B. Autocrine signaling analysis of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways found PDGF D-specific activation of the c-jun-NH2-kinase (JNK) signaling cascade. Using short hairpin RNA and pharmacologic inhibitors, we showed that PDGFD-mediated phenotypic transformation is β-PDGFR and JNK dependent. Importantly, we made a novel finding of PDGF D-specific increase in the shedding and activation of the serine protease matriptase in prostate epithelial cells. Our study, for the first time to our knowledge, showed ligand-specific β-PDGFR signaling as well as PDGF D-specific regulation of matriptase activity and its spatial distribution through shedding. Taken together with our previous finding that matriptase is a proteolytic activator of PDGF D, this study provides a molecular insight into signal amplification of the proteolytic network and PDGF signaling loop during cancer progression.

• Authors: Abdo J Najy, Joshua J Won, Lisa S Movilla, Hyeong-Reh C Kim
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 10 Issue 8 Pg. 1087-97 (Aug 2012) ISSN: 1557-3125 [Electronic] United States
• PMID: 22689130 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Lymphokines
• PDGFD protein, human
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Becaplermin
• Receptor, Platelet-Derived Growth Factor beta
• Mitogen-Activated Protein Kinase Kinases
• Serine Endopeptidases
• matriptase

Topics

• Animals
• Becaplermin
• Cell Line, Tumor
• Cell Movement
• Cell Transformation, Neoplastic
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphokines (genetics, metabolism)
• Male
• Mice
• Mice, SCID
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Neoplasm Invasiveness
• Platelet-Derived Growth Factor (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism)
• Proto-Oncogene Proteins c-sis (genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)
• Serine Endopeptidases (genetics, metabolism)
• Signal Transduction