Tài liệu Báo cáo khoa học: Efficient killing of SW480 colon carcinoma cells by a signal transducer

Efficient killing of SW480 colon carcinoma cells by a

signal transducer and activator of transcription (STAT) 3

hairpin decoy oligodeoxynucleotide – interference with

interferon-c-STAT1-mediated killing

Ali Tadlaoui Hbibi1,2, Christelle Laguillier1,2, Ine` s Souissi1,2, Denis Lesage1,2, Ste´phanie Le Coquil1,2,

An Cao3

, Valeri Metelev4

, Fanny Baran-Marszak1,2,5 and Remi Fagard1,2,6

1 Institut National de la Sante´ et de la Recherche Me´dicale, U978, Bobigny, France

2 Universite´ Paris 13, UFR SMBH Bobigny, France

3 Centre National de la Recherche Scientifique, UMR 7033, Bobigny, France

4 Department of Chemistry, Moscow State University, Russia

5 AP-HP, hoˆpital Avicenne, service d’he´matologie, Bobigny, France

6 AP-HP, hoˆpital Avicenne, service de biochimie, Bobigny, France

Signal transducer and activators of transcription

(STATs) are a family of transcription factors that are

activated in response to cytokines regulating cell proli￾feration, differentiation, inflammation, the immune

response, apoptosis and fetal development [1]. Sche￾matically, the inactive STATs are cytoplasmic; once

activated, they dimerize and enter the nucleus where

they induce the expression of target genes [2].

Several studies have demonstrated that STAT3 is a

key regulator of cell proliferation. It was shown to be a

Keywords

cell death; hairpin decoy oligonucleotide;

interferon-c; STAT1; STAT3

Correspondence

R. Fagard, service de biochimie, hoˆpital

Avicenne 125 rue de Stalingrad, 93009

Bobigny Cedex, France

Fax: +33 014 895 5627

Tel: +33 014 895 5928

E-mail: remi.fagard@avc.aphp.fr

(Received 17 November 2008, revised 25

January 2009, accepted 19 February 2009)

doi:10.1111/j.1742-4658.2009.06975.x

The signal transducers and activators of transcription (STATs) convey sig￾nals 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-c,

involved in defence against pathogens and the inhibition of cell prolifera￾tion. 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-jB, a key regulator of

cell proliferation, with decoy oligodeoxynucleotides results in cell death.

We used a similar approach for STAT3. A hairpin STAT3 oligodeoxy￾nucleotide 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-c. This effect was counter￾acted 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-c

cell killing, highlighting the need to optimize STAT3-targeting oligodeoxy￾nucleotides.

Abbreviations

FITC, fluorescein isothiocyanate; GAS, c-activated sequence; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; NF, nuclear

factor; ODN, oligodeoxynucleotide; PARP, poly(ADP-ribose) polymerase; STAT, signal transducer and activator of transcription; TEAPC-chol,

3b-[N-(N ¢,N ¢,N ¢-triethylaminopropane)-carbamoyl] cholesterol iodide.

FEBS Journal 276 (2009) 2505–2515 ª 2009 The Authors Journal compilation ª 2009 FEBS 2505