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Mechanisms of cell survival induced by CpG‐DNA
Author(s) -
Chu WenMing,
Dragoi AnaMaria,
Cao Cong,
Wan Yinsheng
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.672.25
Subject(s) - tlr9 , cpg site , toll like receptor 9 , protein kinase b , dna , cpg oligodeoxynucleotide , cancer research , microbiology and biotechnology , chemistry , dna damage , cancer cell , biology , phosphorylation , cancer , dna methylation , biochemistry , gene , genetics , gene expression
CpG‐DNA not only activates immune cells to produce pro‐inflammatory cytokines, but also rescues B cells from spontaneous apoptosis and protects cells from killing by anti‐cancer drugs and UV irradiation. However, whereas the molecular mechanisms of the inflammatory cytokine response to CpG‐DNA have been the subject of intensive investigation, little is known about the action of CpG‐DNA in cell survival. Therefore, we investigated how CpG‐DNA protects cells from killing by anti‐leukemia drug vincristine. We found that CpG‐DNA induced phosphorylation and activation of Akt in either bone marrow‐derived macrophages (BMDMs) or mouse embryonic fibroblasts. Interestingly, DNA‐PK inhibitor Nu7026, but not TLR9 inhibitor chloroquine, severely impaired the phosphorylation and activation of Akt by CpG‐DNA. Dose response and kinetic experiments carried out in our BMDMs system revealed that loss of the catalytic subunit of DNA‐PK (DNA‐PKcs), but not TLR9 or its adaptor protein MyD88, largely impaired phosphorylation of Akt in response to CpG‐DNA. In addition, CpG‐DNA induced activation of downstream events of Akt, which is largely dependent on DNA‐PKcs, but not TLR9 or MyD88. Finally, we found that the axis of DNA‐PKcs/Akt is critical for CpG‐DNA‐induced protection of cells from killing by vincristine. Taken together, our data suggest that Akt and DNA‐PK can be targets for CpG‐DNA in vaccine strategy for cancer.