mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer.
The melanoma differentiation-associated gene (mda-7; approved gene symbol IL24) is a tumor suppressor gene whose protein expression in normal cells is restricted to the immune system and to melanocytes. Recent studies have shown that mda-7 gene transfer inhibits cell growth and induces apoptosis in melanoma, lung cancer, breast cancer, and other tumor types through activation of various intracellular signaling pathways. In the current study, we demonstrate that Ad-mda7 transduction of human pancreatic cancer cells results in G2/M cell cycle arrest and cell killing. Cytotoxicity is mediated via apoptosis in a time- and dose-dependent manner. Tumor cell killing correlates with regulation of proteins involved in the Wnt and PI3K pathways: beta-catenin, APC, GSK-3, JNK, and PTEN. Additionally, we identify bystander cell killing activated by exposure of pancreatic tumor cells to secreted human MDA-7 protein. In pancreatic tumor cells, exogenous MDA-7 protein activates STAT3 and kills cells via engagement of IL-20 receptors. The specificity of bystander killing is demonstrated using neutralizing anti-MDA-7 antibodies and anti-receptor antibodies, which inhibit the apoptotic effects. In sum, we show that Ad-mda7 is able to induce growth inhibition and apoptosis in pancreatic cancer cells via inhibition of the Wnt/PI3K pathways and identify a novel bystander mechanism of MDA-7 killing in pancreatic cancer that functions via IL-20 receptors.
Chada
Sunil
S
Introgen Therapeutics, Houston, TX 77030, USA. s.chada@introgen.com
Bocangel
Dora
D
Ramesh
Rajagopal
R
Grimm
Elizabeth A
EA
Mumm
John B
JB
Mhashilkar
Abner M
AM
Zheng
Mingzhong
M
D017209:Apoptosis; D024201:Bystander Effect; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin; D000099180:Interleukin-24
D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007378:Interleukins; D019869:Phosphatidylinositol 3-Kinases; D018123:Receptors, Interleukin; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D000099180:Interleukin-24; C495270:CTNNB1 protein, human; C492510:interleukin-20 receptor