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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
.
Diseases
Validation
Diseases presenting
"tumor development"
symptom
congenital adrenal hyperplasia
dystrophic epidermolysis bullosa
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
liposarcoma
lymphangioleiomyomatosis
oral submucous fibrosis
primary effusion lymphoma
severe combined immunodeficiency
wolf-hirschhorn syndrome
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