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


METHODS
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.
Shimamura
Takeshi
T
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Fujisawa
Toshio
T
Husain
Syed R
SR
Joshi
Bharat
B
Puri
Raj K
RK
D036002:ADP Ribose Transferases / Q000627:therapeutic use*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001427:Bacterial Toxins / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005098:Exotoxins / Q000502:physiology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D037521:Virulence Factors / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A