Prostaglandin (PG) E(2), a
cyclooxygenase (COX) product, and
angiotensin II are endogenous and have physiological roles in the body. On the other hand, an inducible
isoform of COX (COX-2),
insulin-like growth factor (
IGF) II, and
IGF-I receptor (IGF-IR) are up-regulated in colon
carcinoma and might have crucial roles in
tumor growth and invasion. The aim of the present study was to investigate the effects of
COX-2 inhibitor and drugs blocking the biological activities of
angiotensin II [
angiotensin-converting enzyme (
ACE) inhibitors or
angiotensin II receptor blockers (ARBs)] on IGF-IR expression and
tumor growth in vivo. We also investigated the effects of
PGE(2), a major COX-2 product, in
cancer cells and the effects of
angiotensin II on IGF-IR expression and the underlying mechanism of action. In in vivo studies,
tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. In in vitro studies, the effects of nonsteroidal anti-inflammatory drugs (
NSAIDs) on IGF-IR expression were analyzed in three
colon cancer cell lines (Colon 26, HCA-7, and LS174T).
IGF-II-induced cell growth and invasion were analyzed in Colon 26 cells in the presence and absence of
NSAIDs (
indomethacin and
celecoxib) and
angiotensin II.
Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an
ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of
celecoxib (>20 mg/kg) suppressed
tumor growth. On the other hand, combination
therapy with these two categories of drugs significantly reduced
tumor growth in vivo. Treatment with both
celecoxib and an
ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated
tumor cells. In in vitro studies,
NSAIDs reduced IGF-IR expression in a dose-dependent manner in all three cell lines.
NSAIDs also inhibited
IGF-II-stimulated growth and invasion in a dose-dependent manner.
PGE(2) or
angiotensin II treatment reversed the
NSAID-induced down-regulation of IGF-IR expression, growth, and invasion.
PGE(2) and
angiotensin II induced Akt phosphorylation, and
LY294002 or
wortmannin inhibited PGE(2)- or
angiotensin II-induced IGF-IR expression, indicating that
PGE(2) and
angiotensin II both regulate IGF-IR expression by the same Akt/
phosphatidylinositol-3 pathway. Thus, combination
therapy with
NSAIDs and
ACE inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the
chemoprevention of
colon cancer.