Bystander activity of Ad-mda7: human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism.
The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 family of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 family members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
Chada
Sunil
S
Introgen Therapeutics, Inc., Houston, TX 77030, USA. s.chada@introgen.com
Mhashilkar
Abner M
AM
Ramesh
Rajagopal
R
Mumm
John B
JB
Sutton
R Bryan
RB
Bocangel
Dora
D
Zheng
Mingzhong
M
Grimm
Elizabeth A
EA
Ekmekcioglu
Suhendan
S
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D024201:Bystander Effect / Q000502:physiology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D016753:Interleukin-10 / Q000145:classification / Q000494:pharmacology; D007378:Interleukins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism; D000099180:Interleukin-24
D004268:DNA-Binding Proteins; D016753:Interleukin-10; D007378:Interleukins; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D019892:eIF-2 Kinase; D000099180:Interleukin-24; C494086:STAT3 protein, human; C492510:interleukin-20 receptor