Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Gene transfer of interleukin 13 receptor α2 chain dramatically enhances the antitumor effect of IL-13 receptor–targeted cytotoxin in human prostate cancer xenografts

Cancer Gene Therapy volume 8, pages 861–868 (2001)Cite this article

Abstract

IL-13Rα2 chain, the primary interleukin-13 (IL-13) binding protein, plays an important role in IL-13 binding and internalization. Based on these findings, in our previous study we transiently transfected four cancer cell lines that do not express IL-13Rα2 chain and demonstrated that these cells acquired increased sensitivity to IL-13 receptor–targeted recombinant cytotoxin, IL13-PE38QQR, which is composed of IL-13 and a mutated form of a Pseudomonas exotoxin. Although some prostate cancer cell lines express functional IL-13R, they are not highly sensitive to IL-13 cytotoxin. Here we investigated whether human prostate cancer and normal prostate epithelial cell lines express IL-13Rα2 chain and whether they can be sensitized to the cytotoxic effect of IL-13 cytotoxin after transient or stable gene transfer of IL-13Rα2 chain. Gene transfer of IL-13Rα2 chain improved binding activity of IL-13 and sensitivity to IL-13 cytotoxin in vitro. In vivo experiments demonstrated that gene transfer of IL-13Rα2 chain dramatically enhanced the antitumor activity of IL-13 cytotoxin in human prostate cancer xenograft models. These results suggest that IL-13R–targeted cytotoxin therapy of prostate cancer may be dramatically enhanced by gene transfer of IL-13Rα2 chain and this strategy, the combination of gene therapy and cytotoxin therapy, may be utilized in the treatment of localized prostate cancer. Cancer Gene Therapy (2001) 8, 861–868

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Reynolds T . Prostate cancer: Numbers may not tell the whole story J Natl Cancer Inst 2000 92: 1873–1876

    Article  CAS  Google Scholar 

  2. Davol PA, Frackelton AR Jr . Targeting human prostatic carcinoma through basic fibroblast growth factor receptors in an animal model: characterizing and circumventing mechanisms of tumor resistance Prostate 1999 40: 178–191

    Article  CAS  Google Scholar 

  3. Vitetta ES, Fulton RJ, May RD, Till M, Uhr JM . Redesigning nature's poisons to create antitumor reagents Science 1988 238: 1098–1101

    Article  Google Scholar 

  4. Pastan I, Fitzgerald D . Recombinant toxins for cancer treatment Science 1991 254: 1173–1177

    Article  CAS  Google Scholar 

  5. Uckun FM . Immunotoxins for the treatment of leukemia Br J Haematol 1993 85: 435–438

    Article  CAS  Google Scholar 

  6. Murphy JR, Vanderspek JC . Targeting diphtheria toxin to growth factor receptors Cancer Biol 1995 6: 259–267

    Article  CAS  Google Scholar 

  7. Youle RJ . Immunotoxins for central nervous system malignancy Cancer Biol 1996 7: 65–70

    Article  CAS  Google Scholar 

  8. Puri RK . Development of a recombinant interleukin-4– Pseudomonas exotoxin for therapy of glioblastoma Toxicol Pathol 1999 27: 53–57

    Article  CAS  Google Scholar 

  9. Obiri NI, Debinski W, Leonard WJ, Puri RK . Receptor for interleukin 13: interaction with interleukin 4 by a mechanism that does not involve the common γ chain shared by receptors for interleukins 2, 4, 7, 9, and 15 J Biol Chem 1995 270: 8797–8804

    Article  CAS  Google Scholar 

  10. Debinski W, Obiri NI, Pastan I, Puri RK . A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4 J Biol Chem 1995 270: 16775–16780

    Article  CAS  Google Scholar 

  11. Puri RK, Leland P, Obiri NI, et al . Targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin-13 and a truncated form of Pseudomonas exotoxin A (PE38QQR) Blood 1996 87: 4333–4339

    CAS  PubMed  Google Scholar 

  12. Husain SR, Obiri NI, Gill P, et al . Receptor for interleukin-13 on AIDS-associated Kaposi's sarcoma cells served as a new target for a potent Pseudomonas exotoxin–based chimeric toxin protein Clin Cancer Res 1997 3: 151–156

    CAS  PubMed  Google Scholar 

  13. Husain SR, Puri RK . Interleukin-13 fusion cytotoxin as a potent targeted agent for AIDS–Kaposi's sarcoma xenograft Blood 2000 95: 3506–3513

    CAS  PubMed  Google Scholar 

  14. Joshi BH, Plautz GE, Puri RK . IL-13 receptor α chain: a novel tumor associated transmembrane protein in primary explants of human malignant gliomas Cancer Res 2000 60: 1168–1172

    CAS  PubMed  Google Scholar 

  15. Obiri NI, Leland P, Murata T, Debinski W, Puri RK . The IL-13 receptor structure differs on various cell types and may share more than one component with IL-4 receptor J Immunol 1997 158: 756–764

    CAS  PubMed  Google Scholar 

  16. Obiri NI, Murata T, Debinski W, Puri RK . Modulation of interleukin (IL)-13 binding and signaling by the γc chain of the IL-2 receptor J Biol Chem 1997 272: 20251–20258

    Article  CAS  Google Scholar 

  17. Murata T, Obiri NI, Puri RK . Human ovarian carcinoma cell lines express IL-4 and IL-13 receptors: comparison between IL-4– and IL-13–induced signal transduction Int J Cancer 1997 70: 230–240

    Article  CAS  Google Scholar 

  18. Murata T, Husain SR, Mohri H, Puri RK . Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway Int Immunol 1998 10: 1103–1110

    Article  CAS  Google Scholar 

  19. Murata T, Obiri NI, Puri RK . Structure of and signal transduction through interleukin-4 and interleukin-13 receptors Int J Mol Med 1998 1: 551–557

    CAS  PubMed  Google Scholar 

  20. Aman MJ, Tayebi N, Obiri NI, et al . cDNA cloning and characterization of the human interleukin 13 receptor α chain J Biol Chem 1996 271: 29265–29270

    Article  CAS  Google Scholar 

  21. Hilton DJ, Zhang JG, Metcalf D, et al . Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor Proc Natl Acad Sci USA 1996 93: 497–501

    Article  CAS  Google Scholar 

  22. Miloux B, Laurent P, Bonnin O, et al . Cloning of the human IL-13Rα1 chain and reconstitution with the IL-4Rα of a functional IL-4/IL-13 receptor complex FEBS Lett 1997 401: 163–166

    Article  CAS  Google Scholar 

  23. Caput D, Laurent P, Kaghad M, et al . Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor α chain J Biol Chem 1996 271: 16921–16926

    Article  CAS  Google Scholar 

  24. Kawakami K, Taguchi J, Murata T, Puri RK . The interleukin-13 receptor α2 chain: an essential component for binding and internalization but not for IL-13 induced signal transduction through STAT6 pathway Blood 2001 97: 2673–2679

    Article  CAS  Google Scholar 

  25. Murata T, Obiri NI, Debinski W, Puri RK . Structure of IL-13 receptor: analysis of subunit composition in cancer and immune cells Biochem Biophys Res Commun 1997 238: 90–94

    Article  CAS  Google Scholar 

  26. Kawakami K, Joshi BH, Puri RK . Sensitization of cancer cells to interleukin 13– Pseudomonas exotoxin–induced cell death by gene transfer of interleukin 13 receptor α chain Hum Gene Ther 2000 11: 1829–1835

    Article  CAS  Google Scholar 

  27. Maini A, Hillman G, Haas GP, et al . Interleukin-13 receptors on human prostate carcinoma cell lines represent a novel target for a chimeric protein composed of IL-13 and a mutated form of Pseudomonas exotoxin J Urol 1997 158: 948–953

    Article  CAS  Google Scholar 

  28. Oshima Y, Joshi BH, Puri RK . Conversion of interleukin-13 into a high affinity agonist by a single amino acid substitution J Biol Chem 2000 275: 14375–14380

    Article  CAS  Google Scholar 

  29. Bright RK, Vocke CD, Emmert-Buck MR, et al . Generation and genetic characterization of immortal human prostate epithelial cell lines derived from primary cancer specimens Cancer Res 1997 57: 995–1002

    CAS  PubMed  Google Scholar 

  30. Murata T, Taguchi J, Puri RK . Interleukin-13 receptor α′ but not α chain: a functional component of interleukin-4 receptors Blood 1998 91: 3884–3891

    CAS  PubMed  Google Scholar 

  31. Obiri NI, Hillman GG, Haas GP, Sud S, Puri RK . Expression of high affinity interleukin-4 receptors on human renal carcinoma cells and inhibition of tumor growth in vitro by interleukin-4 J Clin Invest 1993 91: 88–93

    Article  CAS  Google Scholar 

  32. Munson PJ, Rodbard D . Ligand: a versatile computerized approach for characterization of ligand-binding systems Anal Biochem 1980 107: 220–239

    Article  CAS  Google Scholar 

  33. Puri RK, Ogata M, Leland P, Feldman GM, Pastan I . Expression of high affinity IL4 receptors on murine sarcoma cells and receptor mediated cytotoxicity of tumor cells to chimeric protein between IL-4 and Pseudomonas exotoxin Cancer Res 1991 51: 3011–3017

    CAS  PubMed  Google Scholar 

  34. Heyman RA, Borrelli E, Lesley J, et al . Thymidine kinase obliteration: creation of transgenic mice with controlled immune deficiency Proc Natl Acad Sci USA 1989 86: 2698–2702

    Article  CAS  Google Scholar 

  35. Mullen CA, Kilstrup M, Blaese RM . Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system Proc Natl Acad Sci USA 1992 89: 33–37

    Article  CAS  Google Scholar 

  36. Ram Z, Culver KW, Oshiro EM, et al . Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells Nat Med 1997 3: 1354–1361

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Mariko Kawakami for helpful suggestions, Dr. Bharat H. Joshi for providing IL-13 toxin, and Pamela Dover for technical assistance, procurement of reagents, and reading this manuscript. These studies were performed as a part of a collaboration between FDA and NeoPharm Inc. under a Cooperative Research and Development Agreement (CRADA).

Author information

Authors and Affiliations

  1. Division of Cellular and Gene Therapies, Laboratory of Molecular Tumor Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, 20892, Maryland, USA

    Koji Kawakami, Syed R Husain & Raj K Puri

  2. Prostate Cancer Biology, Franz Cancer Research Center, Chiles Research Institute, Portland, 97213, Oregon, USA

    Robert K Bright

Authors
  1. Koji Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Syed R Husain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert K Bright
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raj K Puri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raj K Puri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawakami, K., Husain, S., Bright, R. et al. Gene transfer of interleukin 13 receptor α2 chain dramatically enhances the antitumor effect of IL-13 receptor–targeted cytotoxin in human prostate cancer xenografts. Cancer Gene Ther 8, 861–868 (2001). https://doi.org/10.1038/sj.cgt.7700373

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700373

Keywords

This article is cited by

Search

Advanced search

Quick links