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* Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute and
§ Intramural Research Support Program, SAIC-Frederick, NCI-FCRDC, Frederick, Maryland
Increased expression of prostaglandin endoperoxide H synthase-2 (PGHS-2)
has been implicated in pathological conditions such as inflammatory
bowel diseases and colon cancer. Recently, it has been demonstrated
that inducible nitric oxide synthase (NOS II) expression and nitric
oxide (NO) production are up-regulated in these diseases as well.
However, the apparent link between PGHS-2 and NOS II has not been
thoroughly investigated in nontransformed and nontumorigenic colonic
epithelial cells. In the present study, we examined the concomitant
expression of PGHS-2 and NOS II as well as the production of
prostaglandin E2 (PGE2) and NO in conditionally immortalized mouse
colonic epithelial cells, namely YAMC
(Apc+/+). We found that the induction of
PGHS-2 and generation of PGE2 in these cells by IFN-
and
lipopolysaccharide (LPS) were greatly reduced by two selective NOS II
inhibitors, L-NIL and SMT. To ascertain the effect of NO on PGHS-2
overexpression, we tested NO-releasing compounds, NOR-1 and SNAP, and
found that they caused PGHS-2 expression and PGE2 production. This
effect was abolished by hemoglobin, a NO scavenger. Using
electrophoretic mobility shift assays, we found that both NOR-1 and
SNAP caused ß-catenin/LEF-1 DNA complex formation. Super-shift by
anti-ß-catenin antibody confirmed the presence of ß-catenin in the
complex. Cell fractionation studies indicated that NO donors caused an
increase in free soluble cytoplasmic ß-catenin. This is further
corroborated by the immunocytochemistry data showing the redistribution
of ß-catenin from the predominantly membrane localization into the
cytoplasm and nucleus after treatment with NO donors. To further
explore the possible connection between PGHS-2 expression and
ß-catenin/LEF-1 DNA complex formation, we studied IMCE
(ApcMin/+) cells, a sister cell line of YAMC
with similar genetic background but differing in Apc
genotype and, consequently, their ß-catenin levels. We found that
IMCE cells, in comparison with YAMC cells, had markedly higher
ß-catenin/LEF-1 DNA complex formation under both resting conditions
as well as after induction with NO. In parallel fashion, IMCE cells
expressed significantly higher levels of PGHS-2 mRNA and protein, and
generated more PGE2. Overall, this study suggests that NO may be
involved in PGHS-2 overexpression in conditionally immortalized mouse
colonic epithelial cells. Although the molecular mechanism of the link
is still under investigation, this effect of NO appears directly or
indirectly to be a result of the increase in free soluble ß-catenin
and the formation of nuclear ß-catenin/LEF-1 DNA complex.—Mei,
J. M., Hord, N. G., Winterstein, D. F., Donald, S. P., and Phang, J. M. Expression of prostaglandin endoperoxide H
synthase-2 induced by nitric oxide in conditionally immortalized murine
colonic epithelial cells.
Key Words: PGHS-2 • NOS II • nitric oxide • colonic epithelial cells
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