Oligonucleotides suppress PKB/Akt and act as superinductors of apoptosis in human keratinocytes

DNA oligonucleotides (ODN) applied to an organism are known to modulate the innate and adaptive immune system. Previous studies showed that a CpG-containing ODN (CpG-1-PTO) and interestingly, also a non-CpG-containing ODN (nCpG-5-PTO) suppress inflammatory markers in skin. In the present study it wa...

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Bibliographic Details
Published in:Nucleic acids research 2009-07, Vol.37 (12), p.3850-3864
Main Authors: Kippenberger, Stefan, Müller, Jutta, Schultz, Maike, Dorn, Annette, Bock, Andreas, Aygün, Hüseyin, Thaçi, Diamant, Hofmann, Matthias, Kaufmann, Roland, Bernd, August
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cells, Cultured
DNA - pharmacology
Humans
Keratinocytes - cytology
Keratinocytes - drug effects
Keratinocytes - enzymology
Molecular Biology
Mutation
Myeloid Differentiation Factor 88 - genetics
Myeloid Differentiation Factor 88 - metabolism
Oligodeoxyribonucleotides - chemistry
Oligodeoxyribonucleotides - pharmacology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Receptor, Epidermal Growth Factor - metabolism
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - metabolism
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Summary:DNA oligonucleotides (ODN) applied to an organism are known to modulate the innate and adaptive immune system. Previous studies showed that a CpG-containing ODN (CpG-1-PTO) and interestingly, also a non-CpG-containing ODN (nCpG-5-PTO) suppress inflammatory markers in skin. In the present study it was investigated whether these molecules also influence cell apoptosis. Here we show that CpG-1-PTO, nCpG-5-PTO, and also natural DNA suppress the phosphorylation of PKB/Akt in a cell-type-specific manner. Interestingly, only epithelial cells of the skin (normal human keratinocytes, HaCaT and A-431) show a suppression of PKB/Akt. This suppressive effect depends from ODN lengths, sequence and backbone. Moreover, it was found that TGFα-induced levels of PKB/Akt and EGFR were suppressed by the ODN tested. We hypothesize that this suppression might facilitate programmed cell death. By testing this hypothesis we found an increase of apoptosis markers (caspase 3/7, 8, 9, cytosolic cytochrome c, histone associated DNA fragments, apoptotic bodies) when cells were treated with ODN in combination with low doses of staurosporin, a well-known pro-apoptotic stimulus. In summary the present data demonstrate DNA as a modulator of apoptosis which specifically targets skin epithelial cells.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkp252