Combinatorial screenings in patients: the interleukin-11 receptor alpha as a candidate target in the progression of human prostate cancer.

Abstract

Direct screening of combinatorial peptide libraries in patients may allow the identification of ligands that target biochemical differences in the endothelium of blood vessels. In a screening performed in a patient, we selected and isolated a mimic motif of interleukin 11 (IL-11) from prostate biopsies after an i.v. administration of a phage display peptide library. We also demonstrated that the IL-11 phage mimic (displaying the cyclic nonapeptide CGRRAGGSC) bound specifically to a corresponding IL-11 receptor (IL-11Ralpha). Here we show that IL-11Ralpha is a potential target for intervention in human prostate cancer through morphological and functional analyses. First, a comprehensive serial immunohistochemical analysis of primary and metastatic prostate cancer samples showed increased stage-specific expression of IL-11Ralpha during disease progression. Second, a proapoptotic peptide was specifically targeted and internalized through this functional IL-11Ralpha-based ligand-receptor pair: treatment of prostate cancer cells in vitro with a proapoptotic peptide guided by the CGRRAGGSC peptide to the IL-11Ralpha resulted in dose-dependent apoptosis. Together, these data indicate that the IL-11Ralpha is a candidate target for translational clinical trials against advanced and metastatic prostate cancer. Moreover, our results illustrate the ability of direct combinatorial screening systems in cancer patients for identification of relevant targets in the context of human disease.

• Authors: Amado J Zurita, Patricia Troncoso, Marina Cardó-Vila, Christopher J Logothetis, Renata Pasqualini, Wadih Arap
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 2 Pg. 435-9 (Jan 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 14744752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers, Tumor
• IL11RA protein, human
• Interleukin-11 Receptor alpha Subunit
• Receptors, Interleukin
• Receptors, Interleukin-11

Topics

• Apoptosis
• Biomarkers, Tumor (analysis)
• Cell Line, Tumor
• Disease Progression
• Humans
• Interleukin-11 Receptor alpha Subunit
• Male
• Prostate (immunology)
• Prostatic Neoplasms (genetics, pathology)
• Receptors, Interleukin (analysis, genetics)
• Receptors, Interleukin-11
• Reference Values