title: IL-13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer.
abstract: Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Rα2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Rα2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Rα2-overexpressing and IL-13Rα2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Rα2-positive cells but not in IL-13Rα2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Rα2-positive cells but not in IL-13Rα2-negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL-13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP-1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL-13Rα2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Rα2-negative tumors. Interestingly, the IL-13Rα2-positive tumor bearing mice died earlier than mice with IL-13Rα2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Rα2-positive tumor bearing mice compared to IL-13Rα2-negative tumor mice. IL-13Rα2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Rα2-negative tumors. Taken together, IL-13Rα2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Rα2 might not only directly kill primary tumors but also prevent cancer metastasis.
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Toshio
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D061965:Matrix Metalloproteinase Inhibitors; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases