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Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma.
[primary effusion lymphoma]
Sphingosine
kinase
(
SPHK
)
is
overexpressed
by
a
variety
of
cancers
,
and
its
phosphorylation
of
sphingosine
results
in
accumulation
of
sphingosine-
1
-
phosphate
(
S
1
P
)
and
activation
of
antiapoptotic
signal
transduction
.
Existing
data
indicate
a
role
for
S
1
P
in
viral
pathogenesis
,
but
roles
for
SPHK
and
S
1
P
in
virus-associated
cancer
progression
have
not
been
defined
.
Rare
pathologic
variants
of
diffuse
large
B-
cell
lymphoma
arise
preferentially
in
the
setting
of
HIV
infection
,
including
primary
effusion
lymphoma
(
PEL
)
,
a
highly
mortal
tumor
etiologically
linked
to
the
Kaposi
's
sarcoma
-associated
herpesvirus
(
KSHV
)
.
We
have
found
that
ABC
294640
,
a
novel
clinical-grade
small
molecule
selectively
targeting
SPHK
(
SPHK
2
>
SPHK
1
)
,
induces
dose-dependent
caspase
cleavage
and
apoptosis
for
KSHV
(
+
)
patient-derived
PEL
cells
,
in
part
through
inhibition
of
constitutive
signal
transduction
associated
with
PEL
cell
proliferation
and
survival
.
These
results
were
validated
with
induction
of
PEL
cell
apoptosis
using
SPHK
2
-
specific
siRNA
,
as
well
as
confirmation
of
drug-induced
SPHK
inhibition
in
PEL
cells
with
dose-dependent
accumulation
of
proapoptotic
ceramides
and
reduction
of
intracellular
S
1
P
.
Furthermore
,
we
demonstrate
that
systemic
administration
of
ABC
294640
induces
tumor
regression
in
an
established
human
PEL
xenograft
model
.
Complimentary
ex
vivo
analyses
revealed
suppression
of
signal
transduction
and
increased
KSHV
lytic
gene
expression
within
drug-treated
tumors
,
with
the
latter
validated
in
vitro
through
demonstration
of
dose-dependent
viral
lytic
gene
expression
within
PEL
cells
exposed
to
ABC
294640
.
Collectively
,
these
results
implicate
interrelated
mechanisms
and
SPHK
2
inhibition
in
the
induction
of
PEL
cell
death
by
ABC
294640
and
rationalize
evaluation
of
ABC
294640
in
clinical
trials
for
the
treatment
of
KSHV-associated
lymphoma
.
Diseases
Validation
Diseases presenting
"cancer"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
alpha-thalassemia
benign recurrent intrahepatic cholestasis
cadasil
canavan disease
carcinoma of the gallbladder
cholangiocarcinoma
coats disease
congenital adrenal hyperplasia
congenital diaphragmatic hernia
cowden syndrome
cushing syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erdheim-chester disease
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
familial mediterranean fever
gm1 gangliosidosis
heparin-induced thrombocytopenia
hereditary cerebral hemorrhage with amyloidosis
hirschsprung disease
hodgkin lymphoma, classical
inclusion body myositis
junctional epidermolysis bullosa
kabuki syndrome
kallmann syndrome
kindler syndrome
lamellar ichthyosis
liposarcoma
locked-in syndrome
lymphangioleiomyomatosis
monosomy 21
neuralgic amyotrophy
oculocutaneous albinism
oligodontia
oral submucous fibrosis
papillon-lefèvre syndrome
pendred syndrome
pleomorphic liposarcoma
primary effusion lymphoma
proteus syndrome
pyomyositis
pyruvate dehydrogenase deficiency
severe combined immunodeficiency
sneddon syndrome
systemic capillary leak syndrome
triple a syndrome
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated
