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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2007-02, Vol.56 (2), p.205-215
• Main Authors: Zheng, Mingzhong, Bocangel, Dora, Doneske, Blair, Mhashilkar, Abner, Ramesh, Rajagopal, Hunt, Kelly K, Ekmekcioglu, Suhendan, Sutton, R Bryan, Poindexter, Nancy, Grimm, Elizabeth A, Chada, Sunil
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - immunology; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Cancer therapies; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation; Cytokines; Cytotoxicity; Female; Flow Cytometry; Fluorescent Antibody Technique; Gene therapy; Gene Transfer Techniques; Humans; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukins - antagonists & inhibitors; Interleukins - immunology; Interleukins - metabolism; Kinases; Melanoma; Original; Phosphorylation; Proteins; Receptors, Interleukin - immunology; Receptors, Interleukin - metabolism; Signal transduction
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-006-0175-1

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 G(2)/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 p27(Kip1). 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.