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Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells.
[lymphangioleiomyomatosis]
Lymphangioleiomyomatosis
(
LAM
)
is
a
progressive
neoplastic
disorder
that
leads
to
lung
destruction
and
respiratory
failure
primarily
in
women
.
LAM
is
typically
caused
by
tuberous
sclerosis
complex
2
(
TSC
2
)
mutations
resulting
in
mTORC
1
activation
in
proliferative
smooth
muscle
-like
cells
in
the
lung
.
The
female
predominance
of
LAM
suggests
that
estradiol
contributes
to
disease
development
.
Metabolomic
profiling
identified
an
estradiol-enhanced
prostaglandin
biosynthesis
signature
in
Tsc
2
-
deficient
(
TSC
(
-
)
)
cells
,
both
in
vitro
and
in
vivo
.
Estradiol
increased
the
expression
of
cyclooxygenase-
2
(
COX
-
2
)
,
a
rate-limiting
enzyme
in
prostaglandin
biosynthesis
,
which
was
also
increased
at
baseline
in
TSC-
deficient
cells
and
was
not
affected
by
rapamycin
treatment
.
However
,
both
Torin
1
treatment
and
Rictor
knockdown
led
to
reduced
COX
-
2
expression
and
phospho-
Akt-
S
473
.
Prostaglandin
production
was
also
increased
in
TSC-
deficient
cells
.
In
preclinical
models
,
both
Celecoxib
and
aspirin
reduced
tumor
development
.
LAM
patients
had
significantly
higher
serum
prostaglandin
levels
than
healthy
women
.
15
-
epi-lipoxin-
A
4
was
identified
in
exhaled
breath
condensate
from
LAM
subjects
and
was
increased
by
aspirin
treatment
,
indicative
of
functional
COX
-
2
expression
in
the
LAM
airway
.
In
vitro
,
15
-
epi-lipoxin-
A
4
reduced
the
proliferation
of
LAM
patient-derived
cells
in
a
dose-dependent
manner
.
Targeting
COX
-
2
and
prostaglandin
pathways
may
have
therapeutic
value
in
LAM
and
TSC-related
diseases
,
and
possibly
in
other
conditions
associated
with
mTOR
hyperactivation
.