Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer

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...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 65; no. 12; pp. 5144 - 5152
Main Authors:	FILLEUR, Stephanie, VOLZ, Karl, SHROFF, Emelyn H, VOLPERT, Olga V, NELIUS, Thomas, MIROCHNIK, Yelena, HANHUA HUANG, ZAICHUK, Tetiana A, AYNLERICH, Maria S, BECERRA, Sofia P, YAP, Ronald, VELICEASA, Dorina
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-06-2005
Subjects:	Amino Acid Sequence Angiogenesis Inhibitors - immunology Angiogenesis Inhibitors - pharmacology Animals Antineoplastic agents Biological and medical sciences CASP8 and FADD-Like Apoptosis Regulating Protein Cell Differentiation - immunology Cell Line, Tumor Corneal Neovascularization DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - physiology Endothelial Cells - cytology Endothelial Cells - immunology Epitope Mapping Epitopes - physiology Eye Proteins - immunology Gynecology. Andrology. Obstetrics Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - physiology Male Male genital diseases Medical sciences Mice Mice, Inbred C57BL Molecular Sequence Data Neovascularization, Pathologic - immunology Neovascularization, Pathologic - prevention & control Nephrology. Urinary tract diseases Nerve Growth Factors - immunology NFATC Transcription Factors Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - physiology Peptide Fragments - immunology Peptide Fragments - pharmacology Pharmacology. Drug treatments Prostatic Neoplasms - blood supply Prostatic Neoplasms - immunology Prostatic Neoplasms - pathology Serpins - immunology Transcription Factors - antagonists & inhibitors Transcription Factors - physiology Tumors Tumors of the urinary system Urinary tract. Prostate gland Angiogenesis Urinary system disease Prostate disease Antigenic determinant Pigments Malignant tumor Neovascularization Cell differentiation Differentiation Male genital diseases Prostate cancer
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-04-3744