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A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer.

ABSTRACT: Increasing evidence indicates the significance of platelet-derived growth factor receptor-? (?-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of ?-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for ?-PDGFR activation in PCa was unknown, and recent clinical trials with imatinib mesylate showed limited success due to normal tissue toxicity. Similarly, in spite of mounting evidence indicating the significance of matriptase in PCa, little is known about its substrates or molecular actions during PCa progression. Here, we identified PDGF-D as a ligand for ?-PDGFR in PCa and discovered matriptase as its regulator. Matriptase activates PDGF-D by proteolytic removal of the CUB domain in a 2-step process, creating a hemidimer, followed by growth factor domain dimer (GFD-D) generation. Matriptase can deactivate PDGF-D by further proteolytic cleavage within the GFD, revealing its biphasic regulation. Importantly, PDGF-D/matriptase colocalization is accompanied with ?-PDGFR phosphorylation in human PCa tissues. This study unveiled a novel signaling axis of matriptase/PDGF-D/?-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks.

SUBMITTER: Ustach CV

PROVIDER: S-EPMC3058856 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer.

Ustach Carolyn V CV Huang Wei W Conley-LaComb M Katie MK Lin Chen-Yong CY Che Mingxin M Abrams Judith J Kim Hyeong-Reh Choi HR

Cancer research 20101123 23

Increasing evidence indicates the significance of platelet-derived growth factor receptor-β (β-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of β-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for β-PDGFR activation in PCa was unknown, and recent clinical trials with imatinib mesylate showed limited success due to normal tissue toxicity. Similarly, in spite of mounting evidence indicating the significance of matr ...[more]

PMID: 21098708

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Project description:Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Dataset Information

A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer.

Publications

A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer.

Similar Datasets

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