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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 (?-PDGFR and ?-PDGFR) play an indispensible role in physiologic and pathologic conditions, including tumorigenesis. The transformative ?-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 ?-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 ?-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 ?-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.

SUBMITTER: Najy AJ

PROVIDER: S-EPMC3929081 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Najy Abdo J AJ Won Joshua J JJ Movilla Lisa S LS Kim Hyeong-Reh C HR

Molecular cancer research : MCR 20120611 8

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 ...[more]

PMID: 22689130

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

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

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