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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
RETRACTED: Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation
Stephanie Filleur1, Karl Volz, Thomas Nelius
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Abstract:
Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.
Insights
Pigment epithelial-derived factor (PEDF) fragments show distinct anti-cancer mechanisms. The 34-mer peptide inhibits angiogenesis and induces apoptosis, while the 44-mer peptide promotes neuroendocrine differentiation in prostate cancer cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Pigment epithelial-derived factor (PEDF) is a potent angiogenesis inhibitor and neurotrophic factor.
- PEDF's functions, including blocking vascular leakage, can be mimicked by its 44-mer peptide.
- Understanding PEDF's structure is key to developing novel anti-cancer agents.
Purpose of the Study:
- To identify and characterize novel anti-angiogenic and neurotrophic peptide fragments of PEDF.
- To elucidate the distinct mechanisms of action for these PEDF-derived peptides.
- To evaluate the therapeutic potential of PEDF fragments in blocking tumor progression.
Main Methods:
- Structural analysis of PEDF to identify potential receptor-binding surfaces.
- Generation and testing of peptides representing different regions of the PEDF molecule.
- Assays to assess angioinhibitory, neurotrophic, apoptotic, and differentiation-inducing activities.
- Cell binding studies using endothelial and prostate cancer cells.
- In vivo tumor formation assays.
Main Results:
- Identified novel anti-angiogenic epitopes: 34-mer (residues 24-57) and TGA (residues 16-26).
- The 44-mer peptide (residues 58-101) fragment, ERT (residues 78-94), retained neurotrophic activity.
- The 34-mer and TGA induced PEDF angioinhibitory signals, apoptosis, and nuclear factor of activated T cell deactivation.
- The ERT fragment induced neuronal differentiation and, uniquely, neuroendocrine differentiation in prostate cancer cells.
- PEDF and its active fragments demonstrated tumor formation blocking capabilities.
Conclusions:
- PEDF possesses distinct functional regions mediated by different receptor interactions.
- The 34-mer peptide targets endothelial cells to inhibit angiogenesis and induce apoptosis.
- The 44-mer peptide promotes cancer cell differentiation, offering a novel therapeutic strategy.
- These findings provide a foundation for developing targeted PEDF-based therapies for cancer.
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