Expression of UCP2 is associated with sensitivity to platinum‑based chemotherapy for ovarian serous carcinoma

Kawanishi,Masaru; Fukuda,Takeshi; Shimomura,Masahiro; Inoue,Yuta; Wada,Takuma; Tasaka,Reiko; Yasui,Tomoyo; Sumi,Toshiyuki

doi:10.3892/ol.2018.8598

Expression of UCP2 is associated with sensitivity to platinum‑based chemotherapy for ovarian serous carcinoma

Authors:
- Masaru Kawanishi
- Takeshi Fukuda
- Masahiro Shimomura
- Yuta Inoue
- Takuma Wada
- Reiko Tasaka
- Tomoyo Yasui
- Toshiyuki Sumi
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545‑8585, Japan
Published online on: April 27, 2018 https://doi.org/10.3892/ol.2018.8598
Pages: 9923-9928

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The standard treatment for ovarian serous carcinoma is maximum debulking surgery and platinum‑based chemotherapy. Despite the high response rate for chemotherapy, the majority of patients will be resistant to first‑line agents and the prognosis for these patients is particularly poor. Currently there are no reliable methods to determine or predict platinum resistance. Uncoupling protein 2 (UCP2) is widely expressed in cancer cells and regulates the production of mitochondrial reactive oxygen species (ROS). A reduction in ROS is associated with carcinogenesis and chemoresistance. Downregulation of UCP2 significantly causes increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and platinum sensitivity. The study included 54 patients with ovarian serous carcinoma (FIGO stages III and IV) who were treated at Osaka City University Hospital between January 2005 and December 2012. Patients were divided into a platinum‑sensitive group (n=27) and platinum‑resistant group (n=27) based on the platinum‑free interval, which was calculated from the time of last platinum administration to the time of recurrence. UCP2 expression in human ovarian serous carcinoma cells was inhibited by genipin, and changes in carboplatin sensitivity were examined. The UCP2 weighted score was lower in the platinum‑sensitive group than in the platinum resistant‑group (P=0.005). In addition, patients in the low UCP2 expression group were more sensitive to platinum‑based chemotherapy than those in the high UCP2 expression group (P=0.001). Sensitivity to carboplatin was significantly increased when UCP2 was inhibited in human ovarian serous carcinoma cells in vitro. UCP2 expression may be a predictive marker of the efficacy of platinum‑based chemotherapy for patients with ovarian serous carcinoma.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Borley J, Wilhelm-Benartzi C, Brown R and Ghaem-Maghami S: Does tumour biology determine surgical success in the treatment of epithelial ovarian cancer? A systematic literature review. Br J Cancer. 107:1069–1074. 2012. View Article : Google Scholar : PubMed/NCBI
3	du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, Bowtell D, Brady M, Casado A, Cervantes A, et al: 2004 consensus statements on the management of ovarian cancer: Final document of the 3rd international gynecologic cancer intergroup ovarian cancer consensus conference (GCIG OCCC 2004). Ann Oncol. 16:VII7–VI12. 2005. View Article : Google Scholar
4	Japan society of gynecologic oncology: Formulation committee of the treatment guidelines for ovarian. https://jsgo.or.jp/guideline/ransou2015.htmlSeptember 1–2017
5	Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM and Baergen R: Gynecologic Oncology Group: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A gynecologic oncology group study. J Clin Oncol. 21:3194–3200. 2003. View Article : Google Scholar : PubMed/NCBI
6	Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, Harter P, Pignata S, Pujade-Lauraine E, Sehouli J, et al: Int J Gynecol Cancer. 21:771–775. 2011. View Article : Google Scholar : PubMed/NCBI
7	Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, Jones W, Almadrones L and Lewis JL Jr: J Clin Oncol. 9:389–393. 1991. View Article : Google Scholar : PubMed/NCBI
8	Kyrgiou M, Salanti G, Pavlidis N, Paraskevaidis E and Ioannidis JP: Survival benefits with diverse chemotherapy regimens for ovarian cancer: Meta-analysis of multiple treatments. J Natl Cancer Inst. 98:1655–1663. 2006. View Article : Google Scholar : PubMed/NCBI
9	Pelicano H, Carney D and Huang P: ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 7:97–110. 2004. View Article : Google Scholar : PubMed/NCBI
10	Alexandre J, Batteux F, Nicco C, Chéreau C, Laurent A, Guillevin L, Weill B and Goldwasser F: Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer. 119:41–48. 2006. View Article : Google Scholar : PubMed/NCBI
11	Fruehauf J and Meyskens FL Jr: Reactive oxygen species: A breath of life or death? Clin Cancer Res. 13:789–794. 2007. View Article : Google Scholar : PubMed/NCBI
12	Boss O, Muzzin P and Giacobino JP: The uncoupling proteins, a review. Eur J Endocrinol. 139:1–9. 1998. View Article : Google Scholar : PubMed/NCBI
13	Fleury C and Sanchis D: The mitochondrial uncoupling protein-2: Current status. Int J Biochem Cell Biol. 31:1261–1278. 1999. View Article : Google Scholar : PubMed/NCBI
14	Baffy G: Uncoupling protein-2 and cancer. Mitochondrion. 10:243–252. 2010. View Article : Google Scholar : PubMed/NCBI
15	Echtay KS, Murphy MP, Smith RA, Talbot DA and Brand MD: Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem. 277:47129–47135. 2002. View Article : Google Scholar : PubMed/NCBI
16	Duval C, Nègre-Salvayre A, Dogilo A, Salvayre R, Pénicaud L and Casteilla L: Increased reactive oxygen species production with antisense oligonucleotides directed against uncoupling protein 2 in murine endothelial cells. Biochem Cell Biol. 80:757–764. 2002. View Article : Google Scholar : PubMed/NCBI
17	Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M, et al: Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med. 9:1062–1068. 2003. View Article : Google Scholar : PubMed/NCBI
18	Teshima Y, Akao M, Jones SP and Marban E: Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res. 93:192–200. 2003. View Article : Google Scholar : PubMed/NCBI
19	Horimoto M, Resnick MB, Konkin TA, Routhier J, Wands JR and Baffy G: Expression of uncoupling protein-2 in human colon cancer. Clin Cancer Res. 10:6203–6207. 2004. View Article : Google Scholar : PubMed/NCBI
20	Carretero MV, Torres L, Latasa U, Garcia-Trevijano ER, Prieto J, Mato JM and Avila MA: Transformed but not normal hepatocytes express UCP2. FEBS Lett. 439:55–58. 1998. View Article : Google Scholar : PubMed/NCBI
21	Imai K, Fukuda T, Wada T, Kawanishi M, Tasaka R, Yasui T and Sumi T: UCP2 expression may represent a predictive marker of neoadjuvant chemotherapy effectiveness for locally advanced uterine cervical cancer. Oncol Lett. 14:951–957. 2017. View Article : Google Scholar : PubMed/NCBI
22	Derdák Z, Fülöp P, Sabo E, Tavares R, Berthiaume EP, Resnick MB, Paragh G, Wands JR and Baffy G: Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis. 27:956–961. 2006. View Article : Google Scholar : PubMed/NCBI
23	Collins P, Jones C, Choudhury S, Damelin L and Hodgson H: Increased expression of uncoupling protein 2 in HepG2 cells attenuates oxidative damage and apoptosis. Liver Int. 25:880–887. 2005. View Article : Google Scholar : PubMed/NCBI
24	Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ and Levin B: Bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 55:237–241. 1995.PubMed/NCBI
25	Pozza Dalla E, Fiorini C, Dando I, Menegazzi M, Sgarbossa A, Costanzo C, Palmieri M and Donadelli M: Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine. Biochim Biophys Acta. 1823:1856–1863. 2012. View Article : Google Scholar : PubMed/NCBI
26	Mailloux RJ, Adjeitey CN and Harper ME: Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents. PLoS One. 5:e132892010. View Article : Google Scholar : PubMed/NCBI