Kaempferol, a natural dietary flavonoid, suppresses 17β‑estradiol‑induced survivin expression and causes apoptotic cell death in endometrial cancer

Chuwa,Agapiti Hipoliti; Sone,Kenbun; Oda,Katsutoshi; Tanikawa,Michihiro; Kukita,Asako; Kojima,Machiko; Oki,Shinya; Fukuda,Tomohiko; Takeuchi,Makoto; Miyasaka,Aki; Kashiyama,Tomoko; Ikeda,Yuji; Nagasaka,Kazunori; Mori‑Uchino,Mayuyo; Matsumoto,Yoko; Wada‑Hiraike,Osamu; Kuramoto,Hiroyuki; Kawana,Kei; Osuga,Yutaka; Fujii,Tomoyuki

doi:10.3892/ol.2018.9340

Kaempferol, a natural dietary flavonoid, suppresses 17β‑estradiol‑induced survivin expression and causes apoptotic cell death in endometrial cancer

Authors:
- Agapiti Hipoliti Chuwa
- Kenbun Sone
- Katsutoshi Oda
- Michihiro Tanikawa
- Asako Kukita
- Machiko Kojima
- Shinya Oki
- Tomohiko Fukuda
- Makoto Takeuchi
- Aki Miyasaka
- Tomoko Kashiyama
- Yuji Ikeda
- Kazunori Nagasaka
- Mayuyo Mori‑Uchino
- Yoko Matsumoto
- Osamu Wada‑Hiraike
- Hiroyuki Kuramoto
- Kei Kawana
- Yutaka Osuga
- Tomoyuki Fujii
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Affiliations: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113‑8655, Japan, Kanagawa Health Service Association, Kanagawa 231‑0021, Japan, Department of Obstetrics and Gynecology, Nihon University, Tokyo 173‑8610, Japan
Published online on: August 21, 2018 https://doi.org/10.3892/ol.2018.9340
Pages: 6195-6201

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Abstract

Endometrioid endometrial carcinoma, commonly known as type 1 endometrial cancer, accounts for >80% of endometrial carcinomas and is dependent on estrogen. We recently reported on the prognostic significance of the BIRC5 survivin gene in endometrial cancer. Estradiol induces survivin expression in estrogen receptor‑positive, but not in estrogen receptor‑negative, cancer cells. Kaempferol, a bioflavonoid, reportedly inhibits estrogen receptor‑α (ERα) in hormone receptor‑positive breast cancer cells. However, whether kaempferol‑mediated inhibition of ERα suppresses survivin and induces cell death in endometrial cancer remains unclarified. The present study evaluated the antitumor effects of kaempferol on endometrial cancer cells. Cell viability assays, flow cytometry analysis, western blotting and annexin V analyses were used to analyze the antitumor effects of kaempferol. The results demonstrated that kaempferol successfully suppressed the viability of two ER‑positive endometrial cancer cell lines, with IC50 values of 83 and 65 µM. In addition, kaempferol induced sub‑G1 cell accumulation and apoptotic cell death (P<0.01) in a dose‑dependent manner. Treatment of cells with estradiol significantly induced co‑expression of nuclear ERα and survivin proteins (P<0.001). Further evaluation revealed that kaempferol causes apoptotic cell death largely by suppressing ERα, survivin and Bcl‑2 protein. Therefore, the results of the present study suggested that targeting ERα and survivin with kaempferol may be a novel therapeutic option against endometrial carcinoma.

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1	Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI
2	Schenker JG, Weinstein D and Okon E: Estradiol and testosterone levels in the peripheral and ovarian circulations in patients with endometrial cancer. Cancer. 44:1809–1812. 1979. View Article : Google Scholar : PubMed/NCBI
3	Yang HP, Gonzalez Bosquet J, Li Q, Platz EA, Brinton LA, Sherman ME, Lacey JV Jr, Gaudet MM, Burdette LA, Figueroa JD, et al: Common genetic variation in the sex hormone metabolic pathway and endometrial cancer risk: Pathway-based evaluation of candidate genes. Carcinogenesis. 5:827–833. 2010. View Article : Google Scholar
4	Hernandez E: Pathological findings and prognosis from uterine malignancy. Curr Opinion Obstet Gynecol. 5:480–485. 1993. View Article : Google Scholar
5	Lachance JA, Darus CJ and Rice LW: Surgical management and postoperative treatment of endometrial carcinoma. Rev Obstet Gynecol. 1:97–105. 2008.PubMed/NCBI
6	Chaudhry P and Asselin E: Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr Relat Cancer. 16:363–380. 2009. View Article : Google Scholar : PubMed/NCBI
7	Oda K, Stokoe D, Taketani Y and McCormick F: High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 65:10669–10673. 2005. View Article : Google Scholar : PubMed/NCBI
8	Chen J, Zhao KN, Li R, Shao R and Chen C: Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer. Curr Med Chem. 21:3070–3080. 2014. View Article : Google Scholar : PubMed/NCBI
9	Scully MM, Palacios-Helgeson LK, Wah LS and Jackson TA: Rapid estrogen signaling negatively regulates PTEN activity through phosphorylation in endometrial cancer cells. Horm Cancer. 5:218–231. 2014. View Article : Google Scholar : PubMed/NCBI
10	Jaiswal PK, Goel A and Mittal RD: Survivin: A molecular biomarker in cancer. Indian J Med Res. 141:389–397. 2015. View Article : Google Scholar : PubMed/NCBI
11	Ryan BM, O'Donovan N and Duffy MJ: Survivin: A new target for anti-cancer therapy. Cancer Treat Rev. 35:553–562. 2009. View Article : Google Scholar : PubMed/NCBI
12	Altieri DC: Targeting survivin in cancer. Cancer Lett. 332:225–228. 2013. View Article : Google Scholar : PubMed/NCBI
13	Wang B, Zhao B, North P, Kong A, Huang J and Miao QR: Expression of NgBR is highly associated with estrogen receptor alpha and survivin in breast cancer. PLoS One. 8:e780832013. View Article : Google Scholar : PubMed/NCBI
14	Erkanli S, Kayaselcuk F, Kuscu E, Bagis T, Bolat F, Haberal A and Demirhan B: Expression of survivin, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium. Int J Gynecol Cancer. 16:1412–1418. 2006. View Article : Google Scholar : PubMed/NCBI
15	Chuwa AH, Sone K, Oda K, Ikeda Y, Fukuda T, Wada-Hiraike O, Inaba K, Makii C, Takeuchi M, Oki S, et al: Significance of survivin as a prognostic factor and a therapeutic target in endometrial cancer. Gynecol Oncol. 141:564–569. 2016. View Article : Google Scholar : PubMed/NCBI
16	Luo H, Rankin GO, Li Z, DePriest L and Chen YC: Kaempferol induces apoptosis in ovarian cancer cells through activating p53 in intrinsic pathway. Food Chem. 128:513–519. 2011. View Article : Google Scholar : PubMed/NCBI
17	Hung H: Inhibition of estrogen receptor alpha expression and function in MCF-7 cells by kaempferol. J Cell Physiol. 198:197–208. 2004. View Article : Google Scholar : PubMed/NCBI
18	Luo H, Rankin GO, Liu L, Daddysman MK, Jiang BH and Chen YC: Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutr Cancer. 61:554–563. 2009. View Article : Google Scholar : PubMed/NCBI
19	Chen HJ, Lin CM, Lee CY, Shih NC, Peng SF, Tsuzuki M, Amagaya S, Huang WW and Yang JS: Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells. Oncol Rep. 30:925–932. 2013. View Article : Google Scholar : PubMed/NCBI
20	Kuramoto H, Nishida M, Morisawa T, Hamano M, Hata H, Kato Y, Ohno E and Lida T: Establishment and characterization of human endometrial cancer cell lines. Ann N Y Acad Sci. 622:402–421. 1991. View Article : Google Scholar : PubMed/NCBI
21	Inaba K, Oda K, Aoki K, Sone K, Ikeda Y, Miyasaka A, Kashiyama T, Fukuda T, Makii C, Arimoto T, et al: Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in ovarian carcinoma cells by fluorescence resonance energy transfer imaging. Oncotarget. 7:29577–29591. 2016. View Article : Google Scholar : PubMed/NCBI
22	Fukuda T, Oda K, Wada-Hiraike O, Sone K, Inaba K, Ikeda Y, Makii C, Miyasaka A, Kashiyama T, Tanikawa M, et al: Autophagy inhibition augments resveratrol-induced apoptosis in Ishikawa endometrial cancer cells. Oncol Lett. 12:2560–2566. 2016. View Article : Google Scholar : PubMed/NCBI
23	Stoica GE, Franke TF, Moroni M, Mueller S, Morgan E, Iann MC, Winder AD, Reiter R, Wellstein A, Martin MB and Stoica A: Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene. 22:7998–8011. 2003. View Article : Google Scholar : PubMed/NCBI
24	Sayeed A, Konduri SD, Liu W, Bansal S, Li F and Das GM: Estrogen receptor alpha inhibits p53-mediated transcriptional repression: Implications for the regulation of apoptosis. Cancer Res. 67:7746–7755. 2007. View Article : Google Scholar : PubMed/NCBI
25	Hoffman WH, Biade S, Zilfou JT, Chen J and Murphy M: Transcriptional repression of the anti-apoptotic survivin gene by wild-type p53. J Biol Chem. 277:3247–3257. 2002. View Article : Google Scholar : PubMed/NCBI
26	Johnson ME and Howerth EW: Survivin: A bifunctional inhibitor of apoptosis protein. Vet Pathol. 41:599–607. 2004. View Article : Google Scholar : PubMed/NCBI
27	Mita AC, Mita MM, Nawrocki ST and Giles FJ: Survivin: Key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 14:5000–5005. 2008. View Article : Google Scholar : PubMed/NCBI
28	Raam S, Richardson GS, Bradley F, MacLaughlin D, Sun L, Frankel F and Cohen JL: Translocation of cytoplasmic estrogen receptors to the nucleus: Immunohistochemical demonstration utilizing rabbit antibodies to estrogen receptors of mammary carcinomas. Breast Cancer Res Treat. 3:179–199. 1983. View Article : Google Scholar : PubMed/NCBI
29	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
30	Reed JC: Apoptosis-targeted therapies for cancer. Cancer Cell. 3:17–22. 2003. View Article : Google Scholar : PubMed/NCBI
31	Sawyers C: Targeted cancer therapy. Nature. 432:294–297. 2004. View Article : Google Scholar : PubMed/NCBI
32	Hirschowitz EA, Foody T, Kryscio R, Dickson L, Sturgill J and Yannelli J: Autologous dendritic cell vaccines for non-small-cell lung cancer. J Clin Oncol. 22:2808–2815. 2004. View Article : Google Scholar : PubMed/NCBI
33	Otto K, Andersen MH, Eggert A, Keikavoussi P, Pedersen LØ, Rath JC, Böck M, Bröcker EB, Straten PT, Kämpgen E and Becker JC: Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine. 23:884–889. 2005. View Article : Google Scholar : PubMed/NCBI
34	Li W, Du B, Wang T, Wang S and Zhang J: Kaempferol induces apoptosis in human HCT116 colon cancer cells via the Ataxia-Telangiectasia Mutated-p53 pathway with the involvement of p53 upregulated modulator of apoptosis. Chem Biol Interact. 177:121–127. 2009. View Article : Google Scholar : PubMed/NCBI
35	Kim SH and Choi KC: Anti-cancer effect and underlying mechanism(s) of kaempferol, a phytoestrogen, on the regulation of apoptosis in diverse cancer cell models. Toxicol Res. 29:229–234. 2013. View Article : Google Scholar : PubMed/NCBI
36	Lee CF, Yang JS, Tsai FJ, Chiang NN, Lu CC, Huang YS, Chen C and Chen FA: Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells. Int J Oncol. 48:2007–2014. 2016. View Article : Google Scholar : PubMed/NCBI