title: Human adrenomedullin up-regulates interleukin-13 receptor alpha2 chain in prostate cancer in vitro and in vivo: a novel approach to sensitize prostate cancer to anticancer therapy.
abstract: Interleukin-13 (IL-13) receptor alpha2 (IL-13Ralpha2), 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-13Ralpha2 in a human prostate tumor cell line. Here, we show that IL-13Ralpha2 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-13Ralpha2 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 mug/kg/d every alternate day), >70% reduction of tumor size was observed compared with controls (P <or= 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.
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.forename: Pamela
authors.initials: P
authors.lastname: Leland
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D036002:ADP Ribose Transferases / Q000627:therapeutic use*; D053607:Adrenomedullin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001427:Bacterial Toxins / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000378:metabolism / Q000627:therapeutic use*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation; D037521:Virulence Factors / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D053607:Adrenomedullin; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D012333:RNA, Messenger; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C507862:ADM protein, human