Dioscin suppresses the viability of ovarian cancer cells by regulating the VEGFR2 and PI3K/AKT/MAPK signaling pathways

Guo,Xianqing; Ding,Xiao

doi:10.3892/ol.2018.8454

Dioscin suppresses the viability of ovarian cancer cells by regulating the VEGFR2 and PI3K/AKT/MAPK signaling pathways

Authors:
- Xianqing Guo
- Xiao Ding
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Affiliations: Department of Pharmaceuticals, Qilu Hospital of Shandong University, Qingdao, Shandong 266035, P.R. China, Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Qingdao, Shandong 266035, P.R. China
Published online on: April 10, 2018 https://doi.org/10.3892/ol.2018.8454
Pages: 9537-9542

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Abstract

Diosgenin is a natural steroidal saponin that is extracted from a range of sources, including from fenugreek. It is a critical raw material in the synthesis of steroid hormone drugs, exhibiting antitumor, anti‑inflammatory, antioxidation and a number of other significant pharmacological actions, possessing high pharmaceutical value. The aim of the present study was to investigate the effects of dioscin suppression on ovarian cancer cell growth and the mechanism of apoptosis induction by dioscin in ovarian cancer cells. The results of the present study demonstrated that dioscin decreased viability and induced apoptosis in SKOV3 human ovarian cancer cells in a dose‑dependent manner. Dioscin significantly increased caspase‑3 and caspase‑9 activity, and increased the protein expression of Bax and cleaved poly(ADP‑ribose) polymerase in SKOV3 cells. In addition, dioscin significantly suppressed vascular endothelial growth factor receptor (VEGFR)2, phosphoinositide 3‑kinase (PI3K), phosphorylated AKT and phosphorylated p38 mitogen‑activated protein kinase (MAPK) protein expression in SKOV3 cells. Taken together, to the best of our knowledge, the present study demonstrated for the first time that dioscin suppresses cell viability in ovarian cancer cells by regulating the VEGFR2 and PI3K/AKT/MAPK signaling pathways.

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1	Ren Y, Shi T, Jiang R, Yin S, Wang P and Zang R: Multiple cycles of neoadjuvant chemotherapy associated with poor survival in bulky stage IIIC and IV ovarian cancer. Int J Gynecol Cancer. 25:1398–1404. 2015. View Article : Google Scholar : PubMed/NCBI
2	Falandry C, Weber B, Savoye AM, Tinquaut F, Tredan O, Sevin E, Stefani L, Savinelli F, Atlassi M, Salvat J, et al: Development of a geriatric vulnerability score in elderly patients with advanced ovarian cancer treated with first-line carboplatin: A GINECO prospective trial. Ann Oncol. 24:2808–2813. 2013. View Article : Google Scholar : PubMed/NCBI
3	Fisher M and Gore M: Cost-effectiveness of trabectedin plus pegylated liposomal doxorubicin for the treatment of women with relapsed platinum-sensitive ovarian cancer in the UK: Analysis based on the final survival data of the OVA-301 trial. Value Health. 16:507–516. 2013. View Article : Google Scholar : PubMed/NCBI
4	Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, Luesley D, Perren T, Bannoo S, Mascarenhas M, et al: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. Lancet. 386:249–257. 2015. View Article : Google Scholar : PubMed/NCBI
5	Miyake T, Kumasawa K, Sato N, Takiuchi T, Nakamura H and Kimura T: Soluble VEGF receptor 1 (sFLT1) induces non-apoptotic death in ovarian and colorectal cancer cells. Sci Rep. 6:248532016. View Article : Google Scholar : PubMed/NCBI
6	Camerin GR, Brito AB, Vassallo J, Derchain SF and Lima CS: VEGF gene polymorphisms and outcome of epithelial ovarian cancer patients. Future Oncol. 13:409–414. 2016. View Article : Google Scholar : PubMed/NCBI
7	Kim BR, Yoon K, Byun HJ, Seo SH, Lee SH and Rho SB: The anti-tumor activator sMEK1 and paclitaxel additively decrease expression of HIF-1α and VEGF via mTORC1-S6K/4E-BP-dependent signaling pathways. Oncotarget. 5:6540–6551. 2014. View Article : Google Scholar : PubMed/NCBI
8	Ganta S, Singh A, Patel NR, Cacaccio J, Rawal YH, Davis BJ, Amiji MM and Coleman TP: Development of EGFR-targeted nanoemulsion for imaging and novel platinum therapy of ovarian cancer. Pharm Res. 31:2490–2502. 2014. View Article : Google Scholar : PubMed/NCBI
9	Ranjbar R, Nejatollahi F, Ahmadi Nedaei AS, Hafezi H and Safaie A: Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in patients with serous ovarian carcinoma and their clinical significance. Iran J Cancer Prev. 8:e34282015. View Article : Google Scholar : PubMed/NCBI
10	Kodigepalli KM, Dutta PS, Bauckman KA and Nanjundan M: SnoN/SkiL expression is modulated via arsenic trioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells. FEBS Lett. 587:5–16. 2013. View Article : Google Scholar : PubMed/NCBI
11	Glaysher S, Bolton LM, Johnson P, Atkey N, Dyson M, Torrance C and Cree IA: Targeting EGFR and PI3K pathways in ovarian cancer. Br J Cancer. 109:1786–1794. 2013. View Article : Google Scholar : PubMed/NCBI
12	Wu M, Chen X, Lou J, Zhang S, Zhang X, Huang L, Sun R, Huang P, Wang F and Pan S: TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment. Oncotarget,. 7:44534–44544. 2016.
13	Wang F, Chang Z, Fan Q and Wang L: Epigallocatechin-3-gallate inhibits the proliferation and migration of human ovarian carcinoma cells by modulating p38 kinase and matrix metalloproteinase-2. Mol Med Rep. 9:1085–1089. 2014. View Article : Google Scholar : PubMed/NCBI
14	Lu M, Xiao L, Hu J, Deng S and Xu Y: Targeting of p38 mitogen-activated protein kinases to early growth response gene 1 (EGR-1) in the human paclitaxel-resistance ovarian carcinoma cells. J Huazhong Univ Sci Technolog Med Sci. 28:451–455. 2008. View Article : Google Scholar : PubMed/NCBI
15	Tong Q, Qing Y, Wu Y, Hu X, Jiang L and Wu X: Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways. Toxicol Appl Pharmacol. 281:166–173. 2014. View Article : Google Scholar : PubMed/NCBI
16	Qi M, Yin L, Xu L, Tao X, Qi Y, Han X, Wang C, Xu Y, Sun H, Liu K and Peng J: Dioscin alleviates lipopolysaccharide-induced inflammatory kidney injury via the microRNA let-7i/TLR4/MyD88 signaling pathway. Pharmacol Res. 111:509–522. 2016. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, He QY and Chiu JF: Dioscin induced activation of p38 MAPK and JNK via mitochondrial pathway in HL-60 cell line. Eur J Pharmacol. 735:52–58. 2014. View Article : Google Scholar : PubMed/NCBI
18	Smith HO, Moon J, Wilczynski SP, Tiersten AD, Hannigan EV, Robinson WR, Rivkin SE, Anderson GL, Liu PY and Markman M: Southwest oncology group trial S9912: Intraperitoneal cisplatin and paclitaxel plus intravenous paclitaxel and pegylated liposomal doxorubicin as primary chemotherapy of small-volume residual stage III ovarian cancer. Gynecol Oncol. 114:206–209. 2009. View Article : Google Scholar : PubMed/NCBI
19	Noonan AM, Bunch KP, Chen JQ, Herrmann MA, Lee JM, Kohn EC, O'Sullivan CC, Jordan E, Houston N, Takebe N, et al: Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer. Cancer. 122:588–597. 2016. View Article : Google Scholar : PubMed/NCBI
20	Adham SA, Sher I and Coomber BL: Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells. Lab Invest. 90:709–723. 2010. View Article : Google Scholar : PubMed/NCBI
21	Lu W, Chen H, Yel F, Wang F and Xie X: VEGF induces phosphorylation of STAT3 through binding VEGFR2 in ovarian carcinoma cells in vitro. Eur J Gynaecol Oncol. 27:363–369. 2006.PubMed/NCBI
22	Barua A, Yellapa A, Bahr JM, Machado SA, Bitterman P, Basu S, Sharma S and Abramowicz JS: VEGFR2-targeted ultrasound imaging agent enhances the detection of ovarian tumors at early stage in laying hens, a preclinical model of spontaneous ovarian cancer. Ultrason Imaging. 37:224–237. 2015. View Article : Google Scholar : PubMed/NCBI
23	Ye J, Chen W, Wu ZY, Zhang JH, Fei H, Zhang LW, Wang YH, Chen YP and Yang XM: Upregulated CTHRC1 promotes human epithelial ovarian cancer invasion through activating EGFR signaling. Oncol Rep. 36:3588–3596. 2016. View Article : Google Scholar : PubMed/NCBI
24	Baron AT, Wilken JA, Haggstrom DE, Goodrich ST and Maihle NJ: Clinical implementation of soluble EGFR (sEGFR) as a theragnostic serum biomarker of breast, lung and ovarian cancer. IDrugs. 12:302–308. 2009.PubMed/NCBI
25	Zhao J, Klausen C, Qiu X, Cheng JC, Chang HM and Leung PC: Betacellulin induces slug-mediated down-regulation of E-cadherin and cell migration in ovarian cancer cells. Oncotarget. 7:28881–28890. 2016.PubMed/NCBI
26	Hsieh MJ, Tsai TL, Hsieh YS, Wang CJ and Chiou HL: Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines. Arch Toxicol. 87:1927–1937. 2013. View Article : Google Scholar : PubMed/NCBI
27	Malm SW, Hanke NT, Gill A, Carbajal L and Baker AF: The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines. J Exp Clin Cancer Res. 34:312015. View Article : Google Scholar : PubMed/NCBI
28	Xu W, Gu J, Ren Q, Shi Y, Xia Q and Wang J, Wang S, Wang Y and Wang J: NFATC1 promotes cell growth and tumorigenesis in ovarian cancer up-regulating c-Myc through ERK1/2/p38 MAPK signal pathway. Tumour Biol. 37:4493–4500. 2016. View Article : Google Scholar : PubMed/NCBI
29	Watson JL, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA and Hoskin DW: Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling. Mol Carcinog. 49:13–24. 2010.PubMed/NCBI
30	Zhang B, Wang X, Cai F, Chen W, Loesch U and Zhong XY: Antitumor properties of salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and in vivo: Involvement of p38 MAPK activation. Oncol Rep. 29:1371–1378. 2013. View Article : Google Scholar : PubMed/NCBI
31	Buldak RJ, Polaniak R, Buldak L, Mielanczyk L, Kukla M, Skonieczna M, Dulawa-Buldak A, Matysiak N and Zwirska-Korczala K: Exogenous administration of visfatin affects cytokine secretion and increases oxidative stress in human malignant melanoma Me45 cells. J Physiol Pharmacol. 64:377–385. 2013.PubMed/NCBI