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Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants.
[cowden syndrome]
Cowden
syndrome
(
CS
)
,
a
Mendelian
autosomal-dominant
disorder
,
predisposes
to
breast
,
thyroid
,
and
other
cancers
.
Germline
variations
in
succinate
dehydrogenase
genes
(
SDHx
)
occur
in
approximately
10
%
PTEN
mutation
-negative
CS
and
CS
-like
(
CSL
)
individuals
(
SDH
(
var
+
)
)
.
We
previously
showed
that
SDHx
variants
result
in
elevated
reactive
oxygen
species
(
ROS
)
,
disruption
of
nicotinamide
adenine
dinucleotide
(
NAD
)
equilibrium
,
and
destabilization
of
p
53
hence
apoptosis
resistance
in
CS
/
CSL
patient-derived
lymphoblastoid
cells
.
In
the
present
study
,
we
sought
to
address
the
tumorigenic
impacts
of
increased
ROS
and
the
potential
of
protecting
SDH
(
var
+
)
cells
with
antioxidants
.
We
measured
the
lipid
peroxidation
levels
in
patient-derived
SDH
(
var
+
)
lymphoblastoid
cells
and
sequenced
74
controls
or
SDH
(
var
+
)
germline
DNA
samples
for
mitochondrial
hypervariable
region
II
(
HVRII
)
polymorphisms
.
SDH
(
var
+
)
lymphoblastoid
cells
were
treated
with
various
antioxidants
to
check
p
53
expression
and
sub-
G
(
1
)
cell
population
with
cell-cycle
analysis
.
We
showed
that
elevated
ROS
results
in
higher
lipid
peroxidation
in
SDH
(
var
+
)
cells
.
Accumulation
of
polymorphisms
in
mitochondrial
HVRII
was
observed
in
SDH
(
var
+
)
samples
.
Interestingly
,
α-tocopherol
(
vitamin
E
)
treatment
,
but
not
other
antioxidants
,
rescued
SDH
(
var
+
)
cells
from
apoptosis
resistance
and
protected
SDH
(
var
+
)
cells
from
oxidative
damage
such
as
decreased
lipid
peroxidation
as
well
as
partially
recovered
p
53
expression
and
NAD
/
NADH
levels
.
We
conclude
that
disruption
of
complex
II
because
of
SDHx
variants
leads
to
increased
ROS
generation
,
specifically
accompanied
by
lipid
peroxidation
.
The
lipid
soluble
antioxidant
α-tocopherol
can
selectively
protect
SDH
(
var
+
)
cells
from
oxidative
damage
,
apoptosis
resistance
,
and
rebalance
redox
metabolites
NAD
/
NADH
.
Diseases
Validation
Diseases presenting
"rescued sdh"
symptom
cowden syndrome
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