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: Bharat H Joshi, Pamela Leland, Alfonso Calvo, Jeffrey E Green, Raj K Puri
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 22 Pg. 9311-7 (Nov 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 19010904 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• ADM protein, human
• Bacterial Toxins
• Exotoxins
• Immunotoxins
• Interleukin-13
• Interleukin-13 Receptor alpha2 Subunit
• RNA, Messenger
• Virulence Factors
• Adrenomedullin
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases (therapeutic use)
• Adrenomedullin (analysis, genetics, physiology)
• Animals
• Bacterial Toxins (therapeutic use)
• Cell Line, Tumor
• Exotoxins (therapeutic use)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunotoxins (therapeutic use)
• Interleukin-13 (metabolism, therapeutic use)
• Interleukin-13 Receptor alpha2 Subunit (genetics)
• Male
• Mice
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• RNA, Messenger (analysis)
• Up-Regulation
• Virulence Factors (therapeutic use)