We investigated the mechanisms of the inhibitory effect of
carbonyl reductase 1 (CR1) on
ovarian cancer growth mediated by the activation of the
tumor necrotic factor receptor (TNFR) pathway. OVCAR-3 and TOV21G cells overexpressing CR1 were constructed by transfecting them with CR1
cDNA by lipofection. CR1-overexpressing and control OVCAR-3 and TOV21G cells were injected subcutaneously into nude mice and the
tumor growth was compared between the two groups for 3-4 weeks. The expression of
TNFR1 and
TNFR2 in
tumors was examined immunohistochemically at the end of the experiment. Expression levels of
caspase-8 and -3 activated by
TNFR1, c-Jun activated by
TNFR2, and NF-κB activated by both
TNFR1 and
TNFR2 were determined using immunohistochemistry and western blot analysis.
Tumor growth was significantly suppressed in mice injected with CR1-overexpressing cells.
Tumor volume in the CR1 induction group decreased temporarily until 2 weeks.
Tumor cell membranes in both CR1 induction and control groups were positive for
TNFR1 expression; however, total
protein levels did not differ between the two groups. TNFR-2 expression was comparatively weak in both groups. The expression of NF-κB and c-Jun was weaker in the CR1 induction group than in control. In contrast,
caspase-8 and -3 expression was higher in the CR1 induction group. Furthermore, the number of apoptotic cells was significantly greater in
tumors that appeared after
injections of both types of CR1-overexpressing cells than in those of control
cancer cells. These results suggest that CR1 induces apoptosis by activating the
caspase pathway via binding to
TNFR1.