Inhibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor receptor signaling.
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.
Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
Rie
R
Miura
Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
Yoshihito
Y
Yokoyama
Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
Tatsuhiko
T
Shigeto
Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
Masayuki
M
Futagami
Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
Hideki
H
Mizunuma
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D018124:Receptors, Tumor Necrosis Factor; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human