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Human Adrenomedullin Up-regulates Interleukin-13 Receptor 2 Chain in Prostate Cancer In vitro and In vivo: A Novel Approach to Sensitize Prostate Cancer to Anticancer Therapy

¹ Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration; ² Laboratory of Cell Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland and ³ Department of Histology and Pathology, University of Navarra, Pamplona, Spain

Requests for reprints: Raj K. Puri, Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Building 29B, Room 2NN20, 29 Lincoln Drive, Bethesda, MD 20892. Phone: 301-827-0471; Fax: 301-827-0449; E-mail: raj.puri{at}fda.hhs.gov.

Key Words: IL-13 receptor • adrenomedullin • gene transfer • immunofluorescence • transcript immunoprecipitation • IL-13PE immunotoxin

Interleukin-13 (IL-13) receptor 2 (IL-13R2), a high-affinity IL-13 binding subunit and a tumor antigen, is amplified in a variety of human tumor cell lines and tumors in vivo. By cDNA microarray, we have shown that gene transfer of human and rat adrenomedullin (AM) up-regulates IL-13R2 in a human prostate tumor cell line. Here, we show that IL-13R2 mRNA and protein are also up-regulated in PC-3 prostate tumor cells by recombinant AM (rAM) and human synthetic AM peptide in a dose-dependent manner in vitro and in vivo in mouse prostate tumor model. The 8- to 10-fold up-regulation of IL-13R2 by rAM or AM peptide in prostate tumor cells in vitro and in vivo increased their sensitivity to IL-13PE cytotoxin consisting of IL-13 and a truncated form of Pseudomonas exotoxin. Immunodeficient mice with established prostate tumors transfected with AM or treated with AM peptide showed reduction in tumor size by intratumoral administration of IL-13PE in a dose-dependent manner. At the highest dose (three 100 µg/kg/d every alternate day), >70% reduction of tumor size was observed compared with controls (P 0.01). These results indicate that two completely unrelated hormones (AM and IL-13) are closely related to each other and that we have identified a novel role of AM in sensitizing certain types of prostate tumors to IL-13R–directed therapeutic agent. [Cancer Res 2008;68(22):9311–7]