1. Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors
- Author
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Jami Mandelin, Richard L. Sidman, Wouter H. P. Driessen, Bettina Proneth, Anna Cecilia Rietz, Sue-Hwa Lin, Nora M. Navone, Wadih Arap, Andrey S. Dobroff, Paul Mathew, Renata Pasqualini, Christopher J. Logothetis, and Marina Cardó-Vila
- Subjects
Male ,Proteomics ,medicine.medical_specialty ,Cell ,Peptide ,Bone Neoplasms ,Mice, SCID ,Biology ,Ligands ,Chromatography, Affinity ,Prostate cancer ,Mice ,In vivo ,Osteogenesis ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Nanotechnology ,alpha-Macroglobulins ,Peptide library ,Receptor ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,chemistry.chemical_classification ,Multidisciplinary ,Cancer ,Biological Sciences ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Receptors, Androgen ,Drug Design ,Cancer research ,Disease Progression ,Drug Screening Assays, Antitumor ,Peptides ,Neoplasm Transplantation ,Protein Binding - Abstract
We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgen-independent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand–receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.
- Published
- 2015