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.
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.
Joshi
Bharat H
BH
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.
Leland
Pamela
P
Calvo
Alfonso
A
Green
Jeffrey E
JE
Puri
Raj K
RK
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
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