Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10.
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.
Zheng
Mingzhong
M
Introgen Therapeutics Inc., 2250 Holcombe Boulevard, Houston, TX 77030, USA.
Bocangel
Dora
D
Doneske
Blair
B
Mhashilkar
Abner
A
Ramesh
Rajagopal
R
Hunt
Kelly K
KK
Ekmekcioglu
Suhendan
S
Sutton
R Bryan
RB
Poindexter
Nancy
N
Grimm
Elizabeth A
EA
Chada
Sunil
S
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
D016753:Interleukin-10; D007378:Interleukins; D018123:Receptors, Interleukin; D000099180:Interleukin-24; C492510:interleukin-20 receptor