title: Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10.
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 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.
authors.affiliation: Introgen Therapeutics Inc., 2250 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Mingzhong
authors.initials: M
authors.lastname: Zheng
authors.forename: Dora
authors.initials: D
authors.lastname: Bocangel
authors.forename: Blair
authors.initials: B
authors.lastname: Doneske
authors.forename: Abner
authors.initials: A
authors.lastname: Mhashilkar
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Ramesh
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.forename: R Bryan
authors.initials: RB
authors.lastname: Sutton
authors.forename: Nancy
authors.initials: N
authors.lastname: Poindexter
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
authors.forename: Sunil
authors.initials: S
authors.lastname: Chada
mesh_terms: D017209:Apoptosis / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism*; D000099180:Interleukin-24
chemical_list: D016753:Interleukin-10; D007378:Interleukins; D018123:Receptors, Interleukin; D000099180:Interleukin-24; C492510:interleukin-20 receptor