Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways.
Experimental evidence documents that the MDA-7/IL-24 protein (an IL-10 family cytokine) binds to IL-20 and IL-22 receptor complexes resulting in the activation of JAK/STAT signaling pathways. Recent published reports utilizing human blood derived primary lymphocytes have provided additional confirmatory evidence relating to the cytokine properties of this molecule. A notable attribute of mda-7/IL-24 is its cancer cell-specific apoptosis inducing capacity, which currently remains incompletely understood. Treatment with distinctive tyrosine kinase inhibitors (Genistein and AG18) or a JAK-selective inhibitor (AG490) did not prevent Ad.mda-7 induced apoptosis in diverse cell lines. In addition, there is no apparent correlation between patterns of expression of IL-20R1, IL-20R2, and IL-22R mRNA and susceptibility to Ad.mda-7 in different cell lines. Furthermore, Ad.mda-7 is able to induce killing in STAT/JAK deficient cells. In contrast, treatment with the p38(MAPK) selective inhibitor SB203580, partially inhibited apoptosis induced by Ad.mda-7 in different cell lines. These results demonstrate for the first time that signaling events leading to susceptibility to Ad.mda-7 induced apoptosis, might be tyrosine kinase independent and can thus be distinguished from its cytokine function related properties mediated by the IL-20/IL-22 receptor complexes that require JAK/STAT kinase activity.
Sauane
Moira
M
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Gopalkrishnan
Rahul V
RV
Lebedeva
Irina
I
Mei
Mei Xin
MX
Sarkar
Devanand
D
Su
Zhao-Zhong
ZZ
Kang
Dong-Chul
DC
Dent
Paul
P
Pestka
Sidney
S
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D002461:Cell Line, Transformed; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D000099180:Interleukin-24
D004791:Enzyme Inhibitors; D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D018123:Receptors, Interleukin; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000099180:Interleukin-24; C415369:interleukin-22 receptor; C422042:interleukin 20