Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer
<p>Abstract</p> <p>Background</p> <p>Interleukin-13 Receptor α2 (IL-13Rα2) is a tumor-associated antigen and target for cancer therapy. Since IL-13Rα2 is heterogeneously overexpressed in a variety of human cancers, it would be highly desirable to uniformly upregulate IL...
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| Format: | Article |
| Language: | English |
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BMC
2011-04-01
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| Series: | Journal of Translational Medicine |
| Online Access: | http://www.translational-medicine.com/content/9/1/37 |
| _version_ | 1811298698210050048 |
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| author | Puri Raj K Joshi Bharat H Fujisawa Toshio |
| author_facet | Puri Raj K Joshi Bharat H Fujisawa Toshio |
| author_sort | Puri Raj K |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Interleukin-13 Receptor α2 (IL-13Rα2) is a tumor-associated antigen and target for cancer therapy. Since IL-13Rα2 is heterogeneously overexpressed in a variety of human cancers, it would be highly desirable to uniformly upregulate IL-13Rα2 expression in tumors for optimal targeting.</p> <p>Methods</p> <p>We examined epigenetic regulation of <it>IL-13Rα2 </it>in a murine model of human pancreatic cancer by Bisulfite-PCR, sequencing for DNA methylation and chromatin immunoprecipitation for histone modification. Reverse transcription-PCR was performed for examining changes in IL-13Rα2 mRNA expression after treatment with histone deacetylase (HDAC) and c-jun inhibitors. <it>In vitro </it>cytotoxicity assays and <it>in vivo </it>testing in animal tumor models were performed to determine whether HDAC inhibitors could enhance anti-tumor effects of IL-13-PE in pancreatic cancer. Mice harboring subcutaneous tumors were treated with HDAC inhibitors systemically and IL-13-PE intratumorally.</p> <p>Results</p> <p>We found that CpG sites in <it>IL-13Rα2 </it>promoter region were not methylated in all pancreatic cancer cell lines studied including IL-13Rα2-positive and IL-13Rα2-negative cell lines and normal cells. On the other hand, histones at IL-13Rα2 promoter region were highly-acetylated in IL-13Rα2-positive but much less in receptor-negative pancreatic cancer cell lines. When cells were treated with HDAC inhibitors, not only histone acetylation but also IL-13Rα2 expression was dramatically enhanced in receptor-negative pancreatic cancer cells. In contrast, HDAC inhibition did not increase IL-13Rα2 in normal cell lines. In addition, c-jun in IL-13Rα2-positive cells was expressed at higher level than in negative cells. Two types of c-jun inhibitors prevented increase of IL-13Rα2 by HDAC inhibitors. HDAC inhibitors dramatically sensitized cancer cells to immunotoxin in the cytotoxicity assay <it>in vitro </it>and increased IL-13Rα2 in the tumors subcutaneously implanted in the immunodeficient animals but not in normal mice tissues. Combination therapy with HDAC inhibitors and immunotoxin synergistically inhibited growth of not only IL-13Rα2-positive but also IL-13Rα2-negative tumors.</p> <p>Conclusions</p> <p>We have identified a novel function of histone modification in the regulation of IL-13Rα2 in pancreatic cancer cell lines <it>in vitro </it>and <it>in vivo</it>. HDAC inhibition provides a novel opportunity in designing combinatorial therapeutic approaches not only in combination with IL-13-PE but with other immunotoxins for therapy of pancreatic cancer and other cancers.</p> |
| first_indexed | 2024-04-13T06:24:05Z |
| format | Article |
| id | doaj.art-ec36aa74590a4519b05ef4a6befb18f3 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-13T06:24:05Z |
| publishDate | 2011-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-ec36aa74590a4519b05ef4a6befb18f32022-12-22T02:58:31ZengBMCJournal of Translational Medicine1479-58762011-04-01913710.1186/1479-5876-9-37Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancerPuri Raj KJoshi Bharat HFujisawa Toshio<p>Abstract</p> <p>Background</p> <p>Interleukin-13 Receptor α2 (IL-13Rα2) is a tumor-associated antigen and target for cancer therapy. Since IL-13Rα2 is heterogeneously overexpressed in a variety of human cancers, it would be highly desirable to uniformly upregulate IL-13Rα2 expression in tumors for optimal targeting.</p> <p>Methods</p> <p>We examined epigenetic regulation of <it>IL-13Rα2 </it>in a murine model of human pancreatic cancer by Bisulfite-PCR, sequencing for DNA methylation and chromatin immunoprecipitation for histone modification. Reverse transcription-PCR was performed for examining changes in IL-13Rα2 mRNA expression after treatment with histone deacetylase (HDAC) and c-jun inhibitors. <it>In vitro </it>cytotoxicity assays and <it>in vivo </it>testing in animal tumor models were performed to determine whether HDAC inhibitors could enhance anti-tumor effects of IL-13-PE in pancreatic cancer. Mice harboring subcutaneous tumors were treated with HDAC inhibitors systemically and IL-13-PE intratumorally.</p> <p>Results</p> <p>We found that CpG sites in <it>IL-13Rα2 </it>promoter region were not methylated in all pancreatic cancer cell lines studied including IL-13Rα2-positive and IL-13Rα2-negative cell lines and normal cells. On the other hand, histones at IL-13Rα2 promoter region were highly-acetylated in IL-13Rα2-positive but much less in receptor-negative pancreatic cancer cell lines. When cells were treated with HDAC inhibitors, not only histone acetylation but also IL-13Rα2 expression was dramatically enhanced in receptor-negative pancreatic cancer cells. In contrast, HDAC inhibition did not increase IL-13Rα2 in normal cell lines. In addition, c-jun in IL-13Rα2-positive cells was expressed at higher level than in negative cells. Two types of c-jun inhibitors prevented increase of IL-13Rα2 by HDAC inhibitors. HDAC inhibitors dramatically sensitized cancer cells to immunotoxin in the cytotoxicity assay <it>in vitro </it>and increased IL-13Rα2 in the tumors subcutaneously implanted in the immunodeficient animals but not in normal mice tissues. Combination therapy with HDAC inhibitors and immunotoxin synergistically inhibited growth of not only IL-13Rα2-positive but also IL-13Rα2-negative tumors.</p> <p>Conclusions</p> <p>We have identified a novel function of histone modification in the regulation of IL-13Rα2 in pancreatic cancer cell lines <it>in vitro </it>and <it>in vivo</it>. HDAC inhibition provides a novel opportunity in designing combinatorial therapeutic approaches not only in combination with IL-13-PE but with other immunotoxins for therapy of pancreatic cancer and other cancers.</p>http://www.translational-medicine.com/content/9/1/37 |
| spellingShingle | Puri Raj K Joshi Bharat H Fujisawa Toshio Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer Journal of Translational Medicine |
| title | Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer |
| title_full | Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer |
| title_fullStr | Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer |
| title_full_unstemmed | Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer |
| title_short | Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer |
| title_sort | histone modification enhances the effectiveness of il 13 receptor targeted immunotoxin in murine models of human pancreatic cancer |
| url | http://www.translational-medicine.com/content/9/1/37 |
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