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 Hbibi
1,2
, Christelle Laguillier
1,2
, Ine
`
s Souissi
1,2
, Denis Lesage
1,2
, Ste
´
phanie Le Coquil
1,2
,
An Cao
3
, Valeri Metelev
4
, Fanny Baran-Marszak
1,2,5
and Remi Fagard
1,2,6
1 Institut National de la Sante
´
et de la Recherche Me
´

pital
Avicenne 125 rue de Stalingrad, 93009
Bobigny Cedex, France
Fax: +33 014 895 5627
Tel: +33 014 895 5928
E-mail:
(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-

including rheumatoid arthritis [20] or atopic dermatitis
[21]. In cancer cell lines, the STAT3 ODNs were shown
to inhibit cell proliferation [18,22].
How the STAT3 decoy ODNs interact with STAT3
within cells, including how they affect its function, has
not been thoroughly investigated. One potential diffi-
culty regarding specific targeting of STAT3 is that it
shares 72% sequence homology with STAT1. STAT3
and STAT1 are generally recognized to be antagonis-
tic, with STAT3 functioning as a proliferation acti-
vator and STAT1 as an inhibitor [23–25], this
antagonism is further illustrated by the fact that cyto-
kines, such as IL-6, which favour cell proliferation,
activate principally STAT3, whereas cytokines, such as
interferon (IFN)-a ⁄ b or IFN-c, which favour cell
death, activate principally STAT1. However, despite
their different functions in cells, STAT3 and STAT1
recognize very similar sequences on the gene promoters
and share common targets; they can also form hetero-
dimers, whose function has not been clearly elucidated.
In the present study, we focussed on the colorectal
carcinoma cell line SW480, in which STAT3 is consti-
tutively activated [26] and found that SW480 cells were
efficiently killed by the hpST3dODN. SW480 cells
were also efficiently killed by IFN-c treatment, and
this action was counteracted by hpST3dODN, which
reduced transcriptional activity and nuclear localiza-
tion of STAT1 after IFN-c treatment. Thus, although
IFN-c treatment did not impair hpST3dODN-induced
cell killing, IFN-c-induced cell killing was impaired by

little effect (Fig. 1C). Kinetic analysis showed that cell
death was undetectable after 12 h, and became detect-
able after 16, 24 and 48 h (Fig. 1B); after 72 h, the
amount of dead cells and debris made it difficult to
count dead cells. Analysis by flow cytometry clearly
showed the cells that had incorporated hpST3dODN
(FITC positive) were those that were dying (PI posi-
tive) (Fig. 1D). hpST3dODN was also applied to the
2C4 fibroblastic cell line in which STAT3 is not consti-
tutively activated. There was no effect on cell viability,
despite the fact that hpST3dODN could efficiently
enter the cells (not shown). However, curcumin, a non-
specific inhibitor [27,28], could kill the cells (Fig. 1E)
as efficiently as SW480 cells (not shown). To further
explore the sensitivity of SW480 cells to STAT3 inhibi-
tion, the inhibitor stattic, which is considered to be
specific to STAT3 [29], was used and trypan blue-
positive cells counted. Increased cell death was
observed (Fig. 1F), thus strengthening the notion that
specific inhibition of STAT3 is sufficient to induce the
death of these cells. Interestingly, in stattic-treated 2C4
STAT3 hairpin decoy oligonucleotide cell killing A. Tadlaoui Hbibi et al.
2506 FEBS Journal 276 (2009) 2505–2515 ª 2009 The Authors Journal compilation ª 2009 FEBS
cells (in which STAT3 is not activated), there were 5%
dead cells with 10 lm stattic, (28% in SW480), 10%
with 15 lm (35% in SW480), 25% with 30 lm (45% in
SW480) and 35% with 40 lm (60% in SW480).
The hairpin STAT3 decoy ODN inhibits the
transcriptional activity of STAT3 and colocalizes
with STAT3 to the cytoplasm of SW480 cells

0
20
40
FITC lab intensity
0.5 1 2
ODN (µg)
15
20
25
0
5
10
ODN (µg)
PI/FITC-pos cells (%)
0.5 1 2 1e
Cont. (µg)
n
20
30
16 24 48 16 24 48 16 24 48
ODN
(2 µg)
Dead cells (%)
15
30
2C4
10
E. Lip ODN cont Curc
Dead cells (%)
Contrn

M, stained with trypan blue and dead cells were counted. To facilitate the comparison of different experiments,
the results are expressed as a percentage.
A. Tadlaoui Hbibi et al. STAT3 hairpin decoy oligonucleotide cell killing
FEBS Journal 276 (2009) 2505–2515 ª 2009 The Authors Journal compilation ª 2009 FEBS 2507
were either not treated (Fig. 2B) or treated with con-
trol ODN (Fig. 2D), phospho-STAT3 was found
within the nucleus.
The hairpin STAT3 decoy ODN also disrupts
IFN-c-induced STAT1 signalling
Because STAT3 and STAT1 share a high degree of
homology and bind to similar promoter sequences, they
are likely to interact with the same ODN. Although
hpST3dODN induced the death of SW480 cells, and
blocked the transcriptional activity of STAT3, it was
important to verify whether, within cells, this ODN was
STAT3-specific or could also interact with STAT1 and
disrupt its signalling. In colorectal carcinoma cells,
treatment with IFN-c sensitizes cells to cytotoxic com-
pounds, and can also induce cell death on its own
[11,25,31,32]. Experiments were performed to determine
whether this was also observed in SW480 cells. IFN-c,
at 200 ngÆmL
)1
for 48 h, efficiently killed the cells; how-
ever, lower concentrations (10 ngÆmL
)1
) and shorter
exposures (4 h) had no effect on cell death (Fig. 3A). In
addition, treatment of the cells with 100–200 ngÆmL
)1

of phospho-STAT3 analysed by fluorescence
microscopy: (B) in nontreated cells, phopho-
STAT3 was cytoplasmic and nuclear; (C) in
hpST3dODN-treated cells, STAT3 was
almost exclusively cytoplasmic and not
detected in the nuclei (arrow); the FITC-
labelled hpST3dODN was also cytoplasmic;
(D) in control ODN-treated cells, phospho-
STAT3 was mostly nuclear, as in control
cells; the ODN was mostly cytoplasmic
(scale bar = 10 lm).
60
70
Dead cells (%)
20
30
40
50
IFN-γ (ng·mL
–1
) 0 10 100 200
0
10
cPARP
cPARP
actin
24 h
48 h
IFN-γ
0 5 20 100 200

zation of STAT1 was also modified by treatment with
hpST3dODN. In IFN-c-treated cells, STAT1 was
detected in the nucleus (Fig. 4B); in cells treated with
hpST3dODN, STAT1 remained in the cytoplasm and
was found to colocalize with ODN (Fig. 4C); and, in
cells treated with control ODN, the nuclear transloca-
tion of STAT1 occurred normally (Fig. 4D). These
observations suggest that hpST3dODN could interfere
with STAT1, a key signalling factor for IFN-c. Accord-
ingly, cell death was analysed in SW480 cells after treat-
ment with IFN-c and the addition of hpST3dODN. In
cells that were treated with IFN-c, the addition of
hpST3dODN reduced cell death by more than 50%
(Fig. 5A); interestingly, such a reduction of IFN-c-
induced cell death was not observed when treating cells
with stattic, a compound that binds the SH2 domain of
STAT3 with high affinity (Fig. 5B).
hpST3dODN binds both STAT3 and STAT1
The results obtained indicate that hpST3dODN is
acting on both STAT3 and STAT1 and that it has
the potential to interfere with the biological activity
of IFN-c. In the SW480 cell line, IFN-c treatment
resulted in the inhibition of the STAT3-dependent
cyclin D1 promoter, and activation of the STAT1-
2000
2500
IRF1
Luciferase activity
(Rlu per µg prot)
No

untreated cells and nuclear location in IFN-c
treated cells (20 ngÆmL
)1
); (C) cytoplasmic
location of phospho-STAT1 (red) in
hpST3dODN-treated (1 lg) SW480 cells that
had been treated with IFN-c (20 ngÆmL
)1
);
the decoy ODN (green) was also cytoplas-
mic; (D) nuclear location of STAT1 (red) in
cells treated with control ODN (green) (scale
bar = 10 lm).
Dead cells (%)
40
20
10
ODN0+ 000+ +0 0
IFN-γ (ng·mL
–1
) 0 0 0 100 200 100 200 100 200
Control 0 0 + 0 0 0 0 + +
30
40
50
60
70
0 0 0 15 15 15
0
10

hpST3dODN, pull-down experiments were performed
using a biotinylated version of this ODN. This was fol-
lowed by gel separation and western blotting with
anti-phospho-STAT1 or anti-phospho-STAT3. The
results obtained show that, in SW480 cells that have
not been stimulated, there is a basal level of binding of
phospho-STAT3 to hpST3dODN. This binding is
increased in cells treated with IL-6 and, to a lesser
extent, in cells treated with IFN-c (Fig. 6C, lanes 1
and 2). On the other hand, binding of phospho-STAT1
is detected only in cells that have been treated with
IFN-c (Fig. 6C, lane 3).
Discussion
In the present study, we observed that a hairpin decoy
ODN targeting STAT3 (hpST3dODN) induces cell
death of the carcinoma cell line SW480, apparently by
trapping STAT3 within the cytoplasm.
The hairpin decoy, but not control ODN, inhibited
cell proliferation, eliminating any possible effects as a
result of the introduction of DNA within cells, and
indicating that, in itself, the interaction of ODN with
STAT3 induced these effects (i.e. inhibition of the
cyclin-D1-dependent promoter, colocalization with
STAT3 and STAT3 binding in pull-down assays). Our
data indicate a correlation between inhibition of
STAT3 by hpST3dODN and induction of cell death.
In addition, they confirm previous observations made
in head and neck nonsquamous carcinoma cell lines,
with a nonhairpin ODN containing the c-activated
sequence (GAS) sequence [18]. Taken together with

–1
)
0
1000
2000
IRF1
A
Western blotting
IFN-γ (ng·mL
–1
)
0 5 20 100 200
P-STAT1
P-STAT3
STAT1
STAT3
Pull-down
P-STAT1
IL6
IFN-γ –– + – +
–+ – + –
P-STAT3
12 3 45
B
C
Fig. 6. Binding of the STAT3 decoy ODN to STAT3 and STAT1. (A)
SW480 cells were transfected with a cyclin D1-luc plasmid (left
panel) or an IRF1-luc plasmid (right panel) and either treated or not
with IFN-c at 100 ngÆmL
)1

port machinery through its hairpin structure. Although
the combination of induced cell death, inhibited tran-
scription activity and nuclear entry strongly indicates
that hpST3dODN functions by preventing nuclear
entry, further studies are required, including cell frac-
tionation assays, to directly demonstrate this proposal
and to identify the cellular components involved.
Nevertheless, these results suggest that nuclear entry of
a decoy ODN is not a prerequisite for the inhibition of
transcription factors, as previously assumed [33].
There is an intriguing similarity between STAT3 and
STAT1. Both factors share activating stimuli and a
high homology of sequence, and they have common
gene targets and recognize very similar consensus
sequences; yet, they have clearly distinct functions in
cells. STAT3 is mostly involved in cell survival and
proliferation, and STAT1 is involved in anti-viral and
immune defence and cell death, in response to interfer-
ons, including IFN-c [34]. Inhibition of STAT1 using
GAS-based decoy ODNs was previously found to effi-
ciently inhibit inflammation-linked processes such as
graft rejection [35,36], arthritis [37] and contact hyper-
sensitivity [38]. The decoy ODN used in these studies
was considered STAT1-specific. However, a recent
study, using a GAS sequence-based nonhairpin decoy
ODN [39] to inhibit STAT3 in head and neck squa-
mous carcinoma cell lines, although demonstrating
inhibition of IFN-c-activated STAT1, concluded that
there was an absence of interference with STAT1-
mediated actions. The present study of the colon

STAT1 in these cells when they are treated with
IFN-c, we can tentatively conclude that it interacts
with the activated forms of STAT3 and STAT1. The
actions of STAT3 and STAT1 are highly entangled,
they also have antagonistic activities, and they regulate
each others activity. Thus, the inhibition of both
factors in vivo may have unpredictible results. For
example, in cardiac ischaemia, the action of STAT3 is
protective and that of STAT1 increases cardiomyocyte
apoptosis [41,42]. Thus, the inhibition of STAT3 using
decoy ODNs that are not strictly STAT3-specific may
lead to unpredictable results (particularly in whole ani-
mals) by impairing the action of STAT1-dependent
interferon.
The results obtained in the present study, including
the ability of the hairpin decoy STAT3 ODN to inhibit
both activated STAT3 and STAT1, also reveal that, in
SW480 cells, survival may depend in part upon an
equilibrium between the two STATs. This equilibrium
is in favour of activated STAT3 in our untreated colo-
carcinoma cells, and is tilted in favour of activated
STAT1 in IFN-c-treated cells. Such an equilibrium
was observed in cells treated with the Janus kinase-
family inhibitor AG490, where only limited potentia-
tion of the pro-apoptotic effect of doxorubicin was
found, whereas inhibition of STAT3 with a dominant
negative or a platinum derivative increased the
pro-apoptotic effect of doxorubicin [43]. Thus, the
efficiency of blocking STAT3 may depend on
the absence of the inhibition of STAT1. Indeed, cell

vated STAT3 and may not inhibit unphosphorylated
STAT3.
Experimental procedures
Cell culture
SW480 (colon), 2C4 (fibrosarcoma) cell lines were grown in
10% FBS ⁄ DMEM (Gibco BRL, Life Technologies, Cergy-
Pontoise, France), 100 UÆmL
)1
penicillin, 10 lgÆmL
)1
strep-
tomycin (Gibco BRL), 1 mm sodium pyruvate (Gibco
BRL), MEM vitamins 100 · (Gibco BRL) and 5 lgÆmL
)1
plasmocin (Cayla InvivoGen, Toulouse, France). Curcumin
was obtained from Acros Organics (Halluin, France).
Synthesis of the hairpin STAT3 decoy ODN
The oligodeoxynucleotides used comprised: RHN(CH
2
)
6
-
CATTTCCCGTAATCGAAGATTACGGGAAATG-(CH
2
)
3
NHR (hpST3dODN), which was derived from the serum-
inducible element of the human c-fos promoter, and
RHN(CH
2

tidylethanolamine, as previously described [25]. Briefly,
TEAPC-Chol and dioleoyl phosphatidylethanolamine were
mixed at a ratio of 1 : 1 (w ⁄ w) and dissolved in chloro-
form. The solution was dried in vacuum. Sterile water was
then added and the mixture was sonicated to clarity for 1 h
in cycles of 15 min. Using light scattering, we found that
the size distribution of the liposomes was unimodal. The
concentration of cationic lipid was monitored by UV spec-
troscopy at 226 nm and the value was used to calculate the
charge ratio, assuming one positive charge for each cationic
lipid molecule.
Transfection using liposomes
Cells were grown in four-well plates to a density of
0.5 · 10
6
cellsÆmL
)1
. When the cells reached 50–60% con-
fluence, they were transfected with hpST3dODN or the
hairpin control ODN (0.5, 1 and 2 lg corresponding to
100, 200 and 400 nm, respectively) in 150 lL of DMEM
medium (without stromal vascular fraction cells) combined
with the liposomes (0.5, 1 or 2 lg of cationic lipid), thus
yielding liposome : ODN ratios of 0.5 : 0.5, 2 : 2, 1 : 0.5
and 1 : 1 (lg ⁄ lg). After 6 h at 37 °C in a humidified 5%
CO
2
incubator, the cells were placed in fresh serum-
containing medium. Expression was analysed after 48 h.
In control experiments, the liposomes were used alone at

Pasteur, Paris, France). The lysates were centrifuged at
18 000 g for 10 min at 4 °C. Supernatants were collected
and assayed for luciferase activity using the Luciferase
Assay kit (Promega, Madison, WI, USA) and a luminome-
ter (Clarity, Fisher Bioblock Scientific, Illkirsch, France).
Protein concentrations were measured using the Bradford
method. Luciferase activity was normalized as relative light
units per lg of total protein in the supernatant. The experi-
ments were performed in triplicate.
Immunofluorescence
Cellular uptake and subcellular localization of the FITC-
labelled hpST3dODN were analysed on cells grown on
glass slides (Lab-Tek; Nunc, Rochester, NY, USA). Cells
were washed twice in NaCl ⁄ P
i
, fixed in 3.7% formaldehyde
in NaCl ⁄ P
i
for 15 min, permeabilized in 0.1% Triton X-100
for 15 min and blocked with 5% FBS, 0.1% Tween in
NaCl ⁄ Pi for 1 h. Cells were incubated with the primary
antibody (anti-STAT3, anti-STAT1; Cell Signaling Tech-
nology, Beverly, MA, USA; dilution 1 : 100) for 2 h. Alexa
Fluor 546-labelled secondary anti-rat serum (Invitrogen-
Molecular Probes, Carlsbad, CA, USA) at 1 : 250 was
added for 90 min. After counterstaining with 4¢,6¢-diami-
dino-2-phenylindole, coverslips were mounted onto glass
slides in Vectashield (Vectorlabs, Clinisciences, Montrouge,
France). Fluorescence images were digitally acquired using
a Zeiss Axioplan2 Deconvolution microscope (CarlZeiss,

analysed by chemiluminescence (LumiGLO; Cell Signaling
Technology) and autoradiography (X-Omat R; Eastman
Kodak, Rochester, NY, USA).
Acknowledgements
A.T.H. was supported in part by the Fondation
Martine Midy. This work was supported in part by
grants from the Association de recherche contre le
cancer (ARC, grant 3133) and RFBR 06-04-49196.
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