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Rapamycin-resistant PARP1 overexpression is a potential therapeutic target in lymphangioleiomyomatosis (LAM).
[lymphangioleiomyomatosis]
Rationale
:
Lymphangioleiomyomatosis
(
LAM
)
is
a
female
-predominant
cystic
lung
disease
that
can
lead
to
respiratory
failure
.
LAM
cells
typically
have
inactivating
TSC
2
mutations
and
mTORC
1
activation
.
Clinical
response
to
the
mTORC
1
inhibitors
has
been
limited
,
prompting
a
search
for
additional
therapy
for
LAM
.
In
this
study
,
we
investigate
the
impact
of
TSC
2
on
the
expression
of
poly
(
ADP-ribose
)
polymerase-
1
(
PARP
1
)
that
initiates
the
DNA
repair
pathway
and
test
the
efficacy
of
PARP
1
inhibitors
in
the
survival
of
TSC
2
-
deficient
cells
.
Methods
:
We
analyzed
publicly
available
expression
arrays
of
TSC
2
-
deficient
cells
and
validated
the
findings
using
real-time
RT-PCR
,
immunoblotting
,
and
immunohistochemistry
.
We
examined
the
impact
of
rapamycin
and
Torin
1
on
PARP
1
expression
.
We
also
tested
the
effect
of
PARP
1
inhibitors
NU
1025
and
DPQ
on
the
survival
of
TSC
2
-
deficient
cells
.
Results
:
We
identified
the
upregulation
of
PARP
1
in
TSC
2
-
deficient
cells
relative
to
TSC
2
-
addback
cells
.
The
transcript
levels
of
PARP
1
in
TSC
2
-
deficient
cells
were
not
affected
by
rapamycin
.
PARP
1
levels
were
increased
in
TSC
2
-
deficient
cells
,
xenograft
tumors
of
rat-derived
Tsc
2
-
deficient
cells
,
renal
cystadenomas
from
Tsc
2
+
/
-
mice
,
and
human
LAM
nodules
.
RNA
interference
of
mTOR
failed
to
reduce
PARP
1
levels
.
Proliferation
and
survival
of
TSC
2
-
deficient
cells
was
reduced
in
response
to
PARP
1
inhibitor
treatment
,
more
so
than
TSC
2
-
addback
cells
.
Conclusions
:
TSC
2
-
deficient
cells
exhibit
higher
levels
of
PARP
1
relative
to
TSC
2
-
addback
cells
in
an
mTOR-insensitive
manner
.
PARP
1
inhibitors
selectively
suppress
the
growth
and
induce
apoptosis
of
TSC
2
-
deficient
LAM
patient-derived
cells
.
Targeting
PARP
1
may
be
beneficial
in
the
treatment
of
LAM
and
other
neoplasms
with
mTORC
1
activation
.
Diseases
Validation
Diseases presenting
"deficient cells"
symptom
child syndrome
esophageal adenocarcinoma
gm1 gangliosidosis
junctional epidermolysis bullosa
kindler syndrome
lymphangioleiomyomatosis
neonatal adrenoleukodystrophy
werner syndrome
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