Fisetin inhibits the proliferation of gastric cancer cells and induces apoptosis through suppression of ERK 1/2 activation

Yan,Weixin; Chen,Shouhui; Zhao,Yiyang; Ye,Xiaoyu

doi:10.3892/ol.2018.8388

Fisetin inhibits the proliferation of gastric cancer cells and induces apoptosis through suppression of ERK 1/2 activation

Authors:
- Weixin Yan
- Shouhui Chen
- Yiyang Zhao
- Xiaoyu Ye
View Affiliations

Affiliations: Institute of Robotics, School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P.R. China, School of Biomedical Engineering, Med‑X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, UM‑SJTU Joint Institute, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
Published online on: March 29, 2018 https://doi.org/10.3892/ol.2018.8388
Pages: 8442-8446
Copyright: © Yan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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 present study aimed to investigate the effect of fisetin on proliferation and apoptosis of gastric cancer cells, as well as the underlying mechanism. Proliferation in SGC7901 cancer and GES‑1 normal cells was analyzed using a CCK‑8 assay. Apoptosis was analyzed using an Annexin V/Propidium Iodide apoptosis kit and phosphorylation of extracellular signal‑regulated kinase (ERK) 1/2 was analyzed by western blot assay. Treatment of SGC7901 cells with various concentrations (1, 5, 10, 15 and 20 µM) of fisetin for 48 h resulted in a concentration dependent reduction in proliferation. Flow cytometry revealed a marked increase in apoptosis from 5 µM concentration of fisetin after 48 h. The percentage of apoptotic cells increased to 87% following treatment with 15 µM fisetin for 48 h, compared with 2% in control. Treatment of SGC7901 cells with fisetin for 48 h resulted in a reduction in the activation of ERK 1/2 in a concentration‑dependent manner. The reduction in activation of ERK 1/2 was significant following treatment with 15 µM fisetin for 48 h. The inhibitory effect of fisetin on activation of ERK 1/2 was further demonstrated using the ERK 1/2 inhibitor, PD98059. The results indicated a significant reduction in the proliferation of SGC7901 cells following treatment with PD98059 (P<0.002). The reduction by PD98059 administration was comparable to that observed following fisetin treatment for 48 h. In conclusion, the current study demonstrates that fisetin inhibits the proliferation of gastric cancer cells and induces apoptosis through suppression of ERK 1/2 activation. Thus, fisetin may have therapeutic applications in the treatment of gastric cancer.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Aguiar PN Jr, Tadokoro H, Forones NM and de Mello RA: Treating operable patients with gastric cancer: Macdonald's protocol versus adjuvant chemotherapy. Future Oncol. 11:2247–2249. 2015. View Article : Google Scholar : PubMed/NCBI
3	Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: Gastric cancer. Lancet. 374:477–490. 2009. View Article : Google Scholar : PubMed/NCBI
4	Yamamoto M, Sakaguchi Y, Matsuyama A, Yoshinaga K, Tsutsui S and Ishida T: Surgery after preoperative chemotherapy for patients with unresectable advanced gastric cancer. Oncology. 85:241–247. 2013. View Article : Google Scholar : PubMed/NCBI
5	Qiu HB, Zhang LY, Keshari RP, Wang GQ, Zhou ZW, Xu DZ, Wang W, Zhan YQ and Li W: Relationship between H. Pylori infection and clinicopathological features and prognosis of gastric cancer. BMC Cancer. 10:3742010. View Article : Google Scholar : PubMed/NCBI
6	Zhai YK, Pan YL, Niu YB, Li CR, Wu XL, Fan WT, Lu TL, Mei QB and Xian CJ: The importance of the prenyl group in the activities of osthole in enhancing bone formation and inhibiting bone resorption in vitro. Int J Endocrinol. 2014:9219542014. View Article : Google Scholar : PubMed/NCBI
7	Yogesh HS, Chandrashekhar VM, Katti HR, Ganapaty S, Raghavendra HL, Gowda GK and Goplakhrishna B: Anti-osteoporotic activity of aqueous-methanol extract of Berberis aristata in ovariectomized rats. J Ethnopharmacol. 134:334–338. 2011. View Article : Google Scholar : PubMed/NCBI
8	Lee WS, Lee EG, Sung MS and Yoo WH: Kaempferol inhibits IL-1β-stimulated, RANKL-mediated osteoclastogenesis via downregulation of MAPKs, c-Fos, and NFATc1. Inflammation. 37:1221–1230. 2014. View Article : Google Scholar : PubMed/NCBI
9	Tyagi AM, Srivastava K, Singh AK, Kumar A, Changkija B, Pandey R, Lahiri S, Nagar GK, Yadav DK, Maurya R, et al: Formononetin reverses established osteopenia in adult ovariectomized rats. Menopause. 19:856–863. 2012. View Article : Google Scholar : PubMed/NCBI
10	Clardy J and Walsh C: Lessons from natural molecules. Nature. 432:829–837. 2004. View Article : Google Scholar : PubMed/NCBI
11	Tannock IF and Rotin D: Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 49:4373–4384. 1989.PubMed/NCBI
12	Helmlinger G, Yuan F, Dellian M and Jain RK: Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat Med. 3:177–182. 1997. View Article : Google Scholar : PubMed/NCBI
13	Yeo M, Kim DK, Kim YB, Oh TY, Lee JE, Cho SW, Kim HC and Hahm KB: Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells. Clin Cancer Res. 10:8687–8696. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ke Y, Ning T and Wang B: Establishment and characterization of a SV40 transformed human fetal gastric epithelial cell line-GES-1. Zhonghua Zhong Liu Za Zhi. 16:7–10. 1994.(In Chinese). PubMed/NCBI
15	Kim N, Lee SH, Son JH, Lee JM, Kang MJ, Kim BH, Lee JS, Ryu JK and Kim YT: Fisetin reduces cell viability through up-regulation of phosphorylation of ERK1/2 in cholangiocarcinoma cells. Anticancer Res. 36:6109–6116. 2016. View Article : Google Scholar : PubMed/NCBI
16	Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM and Marsh JL: ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Mol Genet. 20:261–270. 2011. View Article : Google Scholar : PubMed/NCBI
17	Holm E, Hagmüller E, Staedt U, Schlickeiser G, Günther HJ, Leweling H, Tokus M and Kollmar HB: Substrate balances across colonic carcinomas in humans. Cancer Res. 55:1373–1378. 1995.PubMed/NCBI
18	Vaupel P, Kallinowski F and Okunieff P: Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res. 49:6449–6465. 1989.PubMed/NCBI
19	Fais S, De Milito A, You H and Qin W: Targeting vacuolar H+-ATPases as a new strategy against cancer. Cancer Res. 67:10627–10630. 2007. View Article : Google Scholar : PubMed/NCBI
20	Danial NN and Korsmeyer SJ: Cell death: Critical control points. Cell. 116:205–219. 2004. View Article : Google Scholar : PubMed/NCBI
21	Kim EK and Choi EJ: Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802:396–405. 2010. View Article : Google Scholar : PubMed/NCBI
22	Zhu P, Chen JM, Guo HM, Fan XP, Zhang XS, Fan RX, Zheng SY, Wu RB, Xiao XJ, Huang HL, et al: Matrine inhibits disturbed flow-enhanced migration via downregulation of ERK1/2-MLCK signaling vascular smooth muscle cells. Ann Vasc Surg. 26:268–275. 2012. View Article : Google Scholar : PubMed/NCBI
23	Ballif BA and Blenis J: Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ. 12:397–408. 2001.PubMed/NCBI