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Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10

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Abstract

The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) family of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G2/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding failed to induce cell killing, indicating that tumor cell killing by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell killing is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited killing mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.

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Acknowledgements

This work was supported by NCI grants CA 89778, CA88421, CA097598, CA102716, CA06294, P30 CA016672-30 and the Cheryl Burguieres Memorial Breast Cancer Fund. We acknowledge the assistance of Ayshwaria Iyer in preparation of this manuscript.

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Authors and Affiliations

  1. Introgen Therapeutics Inc., 2250 Holcombe Boulevard, Houston, TX, 77030, USA

    Mingzhong Zheng, Dora Bocangel, Blair Doneske, Abner Mhashilkar & Sunil Chada

  2. Department of Thoracic and Cardiovascular Surgery, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Rajagopal Ramesh

  3. Department of Surgical Oncology and Tumor Biology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Kelly K. Hunt

  4. Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Suhendan Ekmekcioglu, Nancy Poindexter & Elizabeth A. Grimm

  5. Department of Physiology & Biophysics, UTMB, Galveston, TX, 77555, USA

    R. Bryan Sutton

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  1. Mingzhong Zheng
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Correspondence to Sunil Chada.

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Zheng, M., Bocangel, D., Doneske, B. et al. Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother 56, 205–215 (2007). https://doi.org/10.1007/s00262-006-0175-1

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