Biology Reference
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substance found in tobacco, was found to stimulate angiogenesis and pro-
mote endothelial cell tumor growth through nAChR cross talk with
ARRB1.
59
It was shown that siRNA knockdown of ARRB1 in NSCLC
cells treated with nicotine prevented the activation of Src and Rb-Raf-1
pathways and blocked nicotine-induced proliferation.
35
A later study found
that nicotine stimulation of normal and NSCLC cells promoted the trans-
location of ARRB1 to the nucleus where it bound to E2F transcription fac-
tors. This interaction resulted in the regulation of the proliferative genes,
CDC6 and TYMS, as well as pro-survival genes like BIRC5.
3
The ability
of ARRB1 proteins to translocate to the nucleus, and directly bind and reg-
ulate the activity of transcription factors involved in tumor growth and sur-
vival, validates future studies on determining the potential of inhibiting
ARRB proteins as therapeutic targets.
Tissue microarray analysis revealed that human NSCLC tumors dis-
played increased levels of nuclear ARRB1 compared to normal lung tissue.
3
A recent study investigating the expression levels of ARRB2 in NSCLC by
ELISA found the serum levels of ARRB2 were significantly lower in the
NSCLC patients compared to the healthy control patients. The decreased
serum levels of ARRB2 were also associated with a poorer prognosis in
NSCLC patients.
60
The prostaglandins, that is, PGD
2
,PGE
2
,PGF
2
, and TxA
2
,arecommonly
dysregulated in cancer due to the overexpression of the cyclooxygenase pro-
teins (COX-1 and -2), resulting in increased tumor cell survival, growth,
migration, and invasion.
61,62
The expression of COX-2 protein is increased
in lung cancer, as well as in numerous other cancers.
63,64
The increased
expression results in enhanced PG synthesis. Treatment of lung cancer cells
with PGE
2
resulted in an ARRB-dependent increase in cell migration.
65
In lung cancer cells, PGE
2
bound to the EP4 receptor causing ARRB1
recruitment andmediating the activation of c-Src. Knocking down expression
of ARRB1 with shRNA decreased PGE
2
-mediated c-Src phosphorylation
and migration independent of ERK activation.
65
This makes targeting the
inhibition of ARRB proteins an appealing therapeutic strategy, as it may
reduce tumor cell migration while avoiding the serious adverse side effects that
have been associated with pharmacologic inhibitors of COX-2.
3.4. Bladder cancer
Bladder cancer is the fifth most frequent type of cancer in the United States,
and the National Cancer Institute estimates 73,510 new cases, and 14,880
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