Interleukin 13 mediates signal transduction through interleukin 13 receptor alpha2 in pancreatic ductal adenocarcinoma: role of IL-13 Pseudomonas exotoxin in pancreatic cancer therapy.

Abstract

PURPOSE:

Interleukin-13 receptor alpha2 (IL-13Ralpha2) is a tumor antigen that is overexpressed in certain human tumors. However, its significance and expression in pancreatic cancer is not known. It is also not known whether IL-13 can signal through IL-13Ralpha2 in cancer.

EXPERIMENTAL DESIGN:

The expression of IL-13Ralpha2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13Ralpha2 was examined by IL-13-induced signaling in pancreatic cancer cell lines. IL-13Ralpha2-positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in an orthotopic murine model of human pancreatic cancer.

RESULTS:

Of the pancreatic tumor samples 71% overexpressed moderate to high-density IL-13Ralpha2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-beta1 promoter activity in IL-13Ralpha2-positive tumor cells and in cells engineered to express IL-13Ralpha2 but not in IL-13Ralpha2-negative or RNA interference knockdown cells. c-Jun and c-Fos of the AP-1 family of nuclear factors were activated by IL-13 only in IL-13Ralpha2-positive cells. In the orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole-body imaging and prolonged the mean survival time. Similar results were observed in mice xenografted with a surgically resected human pancreatic tumor sample.

CONCLUSIONS:

These results indicate that IL-13Ralpha2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-beta activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer.

• Authors: Takeshi Shimamura, Toshio Fujisawa, Syed R Husain, Bharat Joshi, Raj K Puri
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 2 Pg. 577-86 (Jan 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20068108 (Publication Type: Journal Article)

Chemical References

• Bacterial Toxins
• Exotoxins
• Interleukin-13
• Interleukin-13 Receptor alpha2 Subunit
• Virulence Factors
• ADP Ribose Transferases

Topics

• ADP Ribose Transferases (therapeutic use)
• Adenocarcinoma (drug therapy, metabolism, pathology)
• Animals
• Bacterial Toxins (therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, metabolism, pathology)
• Exotoxins (physiology, therapeutic use)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interleukin-13 (metabolism, pharmacology, therapeutic use)
• Interleukin-13 Receptor alpha2 Subunit (genetics, metabolism, physiology)
• Mice
• Mice, Nude
• Mice, SCID
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Signal Transduction (drug effects, genetics, physiology)
• Treatment Outcome
• Tumor Cells, Cultured
• Virulence Factors (therapeutic use)
• Xenograft Model Antitumor Assays
• Pseudomonas aeruginosa Exotoxin A