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FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling.
[cholangiocarcinoma]
Interleukin
6
(
IL
-
6
)
-
mediated
signal
transducers
and
activators
of
transcription
3
(
STAT-
3
)
phosphorylation
(
activation
)
is
aberrantly
sustained
in
cholangiocarcinoma
cells
resulting
in
enhanced
myeloid
cell
leukemia
1
(
Mcl-
1
)
expression
and
resistance
to
apoptosis
.
FTY
720
,
a
new
immunosuppressant
,
derived
from
ISP-
1
,
has
been
studied
for
its
putative
anti-
cancer
properties
.
This
study
aimed
to
elucidate
the
mechanism
by
which
FTY
720
mediates
antitumor
effects
in
cholangiocarcinoma
(
CC
)
cells
.
Three
CC
cell
lines
were
examined
,
QBC
939
,
TFK-
1
,
and
HuCCT
1
.
The
therapeutic
effects
of
FTY
720
were
evaluated
in
vitro
and
in
vivo
.
Cell
proliferation
,
apoptosis
,
cell
cycle
,
invasive
potential
,
and
epithelial-
mesenchy-
mal
transition
(
EMT
)
were
examined
.
FTY
720
greatly
inhibited
CC
cells
proliferation
and
EMT
in
vitro
and
in
vivo
,
and
this
effect
was
associated
with
dephosphorylation
of
STAT
3
tyr
705
.
FTY
720
induced
apoptosis
and
G
1
phase
arrest
in
CC
cells
,
and
inhibited
invasion
of
CC
cells
.
Western
blot
analysis
showed
that
FTY
720
induced
cleavage
of
caspases
3
,
8
and
9
,
and
of
PARP
,
in
a
dose-dependent
manner
,
consistent
with
a
substantial
decrease
in
p
-
STAT
3
,
Bcl-x
L
,
Bcl-
2
,
survivin
,
cyclin
D
1
,
cyclin
E
,
N-
cadherin
,
vimentin
,
VEGF
and
TWIST
1
.
In
vivo
studies
showed
that
tumor
growth
and
metastasis
were
significantly
suppressed
after
FTY
720
treatment
.
These
results
suggest
that
FTY
720
induces
a
significant
decrease
in
p
-
STAT
3
,
which
inhibits
proliferation
and
EMT
of
CC
cells
,
and
then
induces
G
1
phase
arrest
and
apoptosis
.
We
have
characterized
a
novel
immunosuppressant
,
which
shows
potential
anti-
tumor
effects
on
CC
via
p
-
STAT
3
inhibition
.
FTY
720
merits
further
investigation
and
warrants
clinical
evaluation
.
Diseases
Validation
Diseases presenting
"tumor effects"
symptom
cholangiocarcinoma
esophageal carcinoma
severe combined immunodeficiency
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