Inhibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor receptor signaling

Miura,Rie; Yokoyama,Yoshihito; Shigeto,Tatsuhiko; Futagami,Masayuki; Mizunuma,Hideki

doi:10.3892/ijo.2015.3205

Inhibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor receptor signaling

Authors:
- Rie Miura
- Yoshihito Yokoyama
- Tatsuhiko Shigeto
- Masayuki Futagami
- Hideki Mizunuma
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Affiliations: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
Published online on: October 13, 2015 https://doi.org/10.3892/ijo.2015.3205
Pages: 2173-2180

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Abstract

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.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, Ngan HY, Pecorelli S and Beller U: Carcinoma of the ovary = FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 95(Suppl 1): S161–S192. 2006. View Article : Google Scholar
3	McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL and Davidson M: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 334:1–6. 1996. View Article : Google Scholar : PubMed/NCBI
4	Yokoyama Y, Xin B, Shigeto T, Umemoto M, Kasai-Sakamoto A, Futagami M, Tsuchida S, Al-Mulla F and Mizunuma H: Clofibric acid, a peroxisome proliferator-activated receptor α ligand, inhibits growth of human ovarian cancer. Mol Cancer Ther. 6:1379–1386. 2007. View Article : Google Scholar : PubMed/NCBI
5	Gonzalez-Covarrubias V, Ghosh D, Lakhman SS, Pendyala L and Blanco JG: A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity. Drug Metab Dispos. 35:973–980. 2007. View Article : Google Scholar : PubMed/NCBI
6	Wermuth B, Bohren KM, Heinemann G, von Wartburg JP and Gabbay KH: Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein. J Biol Chem. 263:16185–16188. 1988.PubMed/NCBI
7	Umemoto M, Yokoyama Y, Sato S, Tsuchida S, Al-Mulla F and Saito Y: Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer. Br J Cancer. 85:1032–1036. 2001. View Article : Google Scholar : PubMed/NCBI
8	Murakami A, Fukushima C, Yoshidomi K, Sueoka K, Nawata S, Yokoyama Y, Tsuchida S, Ismail E, Al-Mulla F and Sugino N: Suppression of carbonyl reductase expression enhances malignant behaviour in uterine cervical squamous cell carcinoma: Carbonyl reductase predicts prognosis and lymph node metastasis. Cancer Lett. 311:77–84. 2011. View Article : Google Scholar : PubMed/NCBI
9	Murakami A, Yakabe K, Yoshidomi K, Sueoka K, Nawata S, Yokoyama Y, Tsuchida S, Al-Mulla F and Sugino N: Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance. Cancer Lett. 323:69–76. 2012. View Article : Google Scholar : PubMed/NCBI
10	Osawa Y, Yokoyama Y, Shigeto T, Futagami M and Mizunuma H: Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation. Int J Oncol. 46:1252–1258. 2015.PubMed/NCBI
11	Wang H, Yokoyama Y, Tsuchida S and Mizunuma H: Malignant ovarian tumors with induced expression of carbonyl reductase show spontaneous regression. Clin Med Insights Oncol. 6:107–115. 2012.PubMed/NCBI
12	Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A and Nagata S: Identification of a factor that links apoptotic cells to phagocytes. Nature. 417:182–187. 2002. View Article : Google Scholar : PubMed/NCBI
13	van Horssen R, Ten Hagen TL and Eggermont AM: TNF-alpha in cancer treatment: Molecular insights, antitumor effects, and clinical utility. Oncologist. 11:397–408. 2006. View Article : Google Scholar : PubMed/NCBI
14	Tracey KJ and Cerami A: Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol. 9:317–343. 1993. View Article : Google Scholar : PubMed/NCBI
15	Vandenabeele P, Declercq W, Beyaert R and Fiers W: Two tumour necrosis factor receptors: Structure and function. Trends Cell Biol. 5:392–399. 1995. View Article : Google Scholar : PubMed/NCBI
16	Rath PC and Aggarwal BB: TNF-induced signaling in apoptosis. J Clin Immunol. 19:350–364. 1999. View Article : Google Scholar
17	Degterev A, Boyce M and Yuan J: A decade of caspases. Oncogene. 22:8543–8567. 2003. View Article : Google Scholar : PubMed/NCBI
18	Barnes PJ and Karin M: Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 336:1066–1071. 1997. View Article : Google Scholar : PubMed/NCBI
19	Karin M, Liu Z and Zandi E: AP-1 function and regulation. Curr Opin Cell Biol. 9:240–246. 1997. View Article : Google Scholar : PubMed/NCBI
20	Rothe M, Pan M-G, Henzel WJ, Ayres TM and Goeddel DV: The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell. 83:1243–1252. 1995. View Article : Google Scholar : PubMed/NCBI
21	Shigeto T, Yokoyama Y, Xin B and Mizunuma H: Peroxisome proliferator-activated receptor α and γ ligands inhibit the growth of human ovarian cancer. Oncol Rep. 18:833–840. 2007.PubMed/NCBI
22	Wakui M, Yokoyama Y, Wang H, Shigeto T, Futagami M and Mizunuma H: Efficacy of a methyl ester of 5-aminolevulinic acid in photodynamic therapy for ovarian cancers. J Cancer Res Clin Oncol. 136:1143–1150. 2010. View Article : Google Scholar : PubMed/NCBI
23	Cebulla J, Huuse EM, Pettersen K, van der Veen A, Kim E, Andersen S, Prestvik WS, Bofin AM, Pathak AP, Bjørkøy G, et al: MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity. Br J Cancer. 112:504–513. 2015. View Article : Google Scholar
24	Hirakawa H, Yokoyama Y, Yoshida H and Mizunuma H: Inhibitory effects of aromatase inhibitor on estrogen receptor-alpha positive ovarian cancer in mice. J Ovarian Res. 7:42014. View Article : Google Scholar : PubMed/NCBI
25	McFarlane SM, Pashmi G, Connell MC, Littlejohn AF, Tucker SJ, Vandenabeele P and MacEwan DJ: Differential activation of nuclear factor-kappaB by tumour necrosis factor receptor subtypes. TNFR1 predominates whereas TNFR2 activates transcription poorly. FEBS Lett. 515:119–126. 2002. View Article : Google Scholar : PubMed/NCBI
26	Wajant H, Pfizenmaier K and Scheurich P: Tumor necrosis factor signaling. Cell Death Differ. 10:45–65. 2003. View Article : Google Scholar : PubMed/NCBI
27	Naudé PJ, den Boer JA, Luiten PG and Eisel UL: Tumor necrosis factor receptor cross-talk. FEBS J. 278:888–898. 2011. View Article : Google Scholar : PubMed/NCBI
28	Zerbini LF, Tamura RE, Correa RG, Czibere A, Cordeiro J, Bhasin M, Simabuco FM, Wang Y, Gu X, Li L, et al: Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-κB inhibitors in ovarian cancer therapy. PLoS One. 6:e242852011. View Article : Google Scholar
29	Nishio H, Yaguchi T, Sugiyama J, Sumimoto H, Umezawa K, Iwata T, Susumu N, Fujii T, Kawamura N, Kobayashi A, et al: Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor. Br J Cancer. 110:2965–2974. 2014. View Article : Google Scholar : PubMed/NCBI
30	Takano M, Sugiyama T, Yaegashi N, Sagae S, Kuzuya K, Udagawa Y, Tsuda H, Suzuki M, Kigawa J, Goto T, et al: Less impact of adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: A retrospective Japan Clear Cell Carcinoma Study. Int J Gynecol Cancer. 20:1506–1510. 2010.PubMed/NCBI