The signal transducers and activators of transcription (STATs) convey signals from the membrane to the nucleus in response to cytokines or growth factors. STAT3 is activated in response to cytokines involved mostly in cell proliferation; STAT1 is activated by cytokines, including interferon‐γ, involved in defence against pathogens and the inhibition of cell proliferation. STAT3, which is frequently activated in tumour cells, is a valuable target with respect to achieving inhibition of tumour cell proliferation. Indeed, its inhibition results in cell death. We previously observed that inhibition of the transcription factor nuclear factor‐κB, a key regulator of cell proliferation, with decoy oligodeoxynucleotides results in cell death. We used a similar approach for STAT3. A hairpin STAT3 oligodeoxynucleotide was added to a colon carcinoma cell line in which it induced cell death as efficiently as the STAT3 inhibitor stattic. The hairpin STAT3 oligodeoxynucleotide co‐localized with STAT3 within the cytoplasm, prevented STAT3 localization to the nucleus, blocked a cyclin D1 reporter promoter and associated with STAT3 in pull‐down assays. However, the same cells were efficiently killed by interferon‐γ. This effect was counteracted by the STAT3 oligodeoxynucleotide, which was found to efficiently inhibit STAT1. Thus, although it can inhibit STAT3, the hairpin STAT3 oligodeoxynucleotide appears also to inhibit STAT1‐mediated interferon‐γ cell killing, highlighting the need to optimize STAT3‐targeting oligodeoxynucleotides.

The transcription factor NF-jB is frequently activated in cancer, and is therefore a valuable target for cancer therapy. Decoy oligodeoxynucleotides (ODNs) inhibit NF-jB by preventing its binding to the promoter region of target genes. Few studies have used NF-jB-targeting with ODNs in cancer. Using a hairpin NF-jB-decoy ODN we found that it induced growth inhibition and cell death in NF-jB-dependent tumour cell lines. The ODN colocalized with the p50 subunit of NF-jB in cells and directly interacted with it in nuclear extracts. In TNFa-treated cells the ODN and the p50 subunit were found in the cytoplasm suggesting that the complex did not translocate to the nucleus. Transcriptional activity of NF-jB was efficiently inhibited by the ODN, whereas a scrambled ODN was without effect on transcription. Thus, ODN-mediated inhibition of NFjB can efficiently promote cell death in cancer cells providing a potentially powerful approach to tumour growth inhibition.

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