Isoliquiritigenin inhibits proliferation and metastasis of MKN28 gastric cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway

Zhang,Xiu‑Rong; Wang,Shi‑Yao; Sun,Wen; Wei,Chao

doi:10.3892/mmr.2018.9318

Isoliquiritigenin inhibits proliferation and metastasis of MKN28 gastric cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway

Authors:
- Xiu‑Rong Zhang
- Shi‑Yao Wang
- Wen Sun
- Chao Wei
View Affiliations

Affiliations: Department of Traditional Chinese Medicine, Maternal and Child Health Care of Shandong Province, Jinan, Shandong 250014, P.R. China, Department of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China, Department of Research, Beijing Splinger Medical Research Institute, Jinan, Shandong 250021, P.R. China, Department of Ophthalmology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
Published online on: July 25, 2018 https://doi.org/10.3892/mmr.2018.9318
Pages: 3429-3436

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

Isoliquiritigenin (ISL) is a ﬂavonoid extracted from licorice root, which is known to serve important antitumor roles in numerous types of cancers; however, its effect on gastric cancer remains to be elucidated. The present study aimed to explore the roles and underlying mechanisms of ISL in MKN28 gastric cancer cells. MKN28 cell proliferation was measured using the Cell Counting Kit‑8 (CCK8) assay. A Transwell assay was used to determine the effects of ISL on the migration and invasion of MKN28 cells. Apoptosis was assessed by flow cytometry, and the expression levels of apoptosis‑, autophagy‑ and signaling pathway‑related proteins were detected by western blot analysis. The results of the CCK8 assay demonstrated that ISL significantly inhibited the proliferation of MKN28 cells (P<0.05). Transwell assays demonstrated that the migration and invasion of MKN28 cells were significantly inhibited following treatment with ISL (P<0.05). Flow cytometric analysis indicated that ISL induced apoptosis of MKN28 cells. In addition, western blot analysis revealed that the ratio of microtubule‑associated proteins 1A/1B light chain 3B (LC3)II/LC3I was upregulated, as was Beclin 1 expression; however, p62 was downregulated following ISL pretreatment, thus suggesting that ISL triggered autophagy in MKN28 cells. In addition, the phosphorylation levels of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were significantly reduced following ISL treatment. These results indicated that ISL may influence apoptosis and autophagy in MKN28 cells by suppressing the phosphoinositide 3‑kinase/AKT/mTOR signaling pathway. In conclusion, the findings of the present study suggested that ISL may inhibit MKN28 cell proliferation, migration and invasion by inducing apoptosis and autophagy, implying potential as a therapeutic agent for gastric cancer.

View Figures

View References

1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2	Lin X, Zhao Y, Song WM and Zhang B: Molecular classification and prediction in gastric cancer. Comput Struct Biotechnol J. 13:448–458. 2015. View Article : Google Scholar : PubMed/NCBI
3	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
4	Liu W, Yang Q, Liu B and Zhu Z: Serum proteomics for gastric cancer. Clin Chim Acta. 431:179–184. 2014. View Article : Google Scholar : PubMed/NCBI
5	Asghari MH, Moloudizargari M, Ghobadi E, Fallah M and Abdollahi M: Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer. Life Sci. 185:38–45. 2017. View Article : Google Scholar : PubMed/NCBI
6	Zheng R, Deng Q, Liu Y and Zhao P: Curcumin inhibits gastric carcinoma cell growth and induces apoptosis by suppressing the Wnt/beta-catenin signaling pathway. Med Sci Monit. 23:163–171. 2017. View Article : Google Scholar : PubMed/NCBI
7	Zheng YB, Xiao GC, Tong SL, Ding Y, Wang QS, Li SB and Hao ZN: Paeoniflorin inhibits human gastric carcinoma cell proliferation through up-regulation of microRNA-124 and suppression of PI3K/Akt and STAT3 signaling. World J Gastroenterol. 21:7197–7207. 2015. View Article : Google Scholar : PubMed/NCBI
8	Shen H, Zhao S, Xu Z, Zhu L, Han Y and Ye J: Evodiamine inhibits proliferation and induces apoptosis in gastric cancer cells. Oncol Lett. 10:367–371. 2015. View Article : Google Scholar : PubMed/NCBI
9	Yeh Feng C, Wang KC, Chiang LC, Shieh DE, Yen MH and Chang San J: Water extract of licorice had anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. J Ethnopharmacol. 148:466–473. 2013. View Article : Google Scholar : PubMed/NCBI
10	Si L, Yang X, Yan X, Wang Y and Zheng Q: Isoliquiritigenin induces apoptosis of human bladder cancer T24 cells via a cyclin-dependent kinase-independent mechanism. Oncol Lett. 14:241–249. 2017. View Article : Google Scholar : PubMed/NCBI
11	Peng F, Du Q, Peng C, Wang N, Tang H, Xie X, Shen J and Chen J: A review: The pharmacology of isoliquiritigenin. Phytother Res. 29:969–977. 2015. View Article : Google Scholar : PubMed/NCBI
12	Zhao Z, Park SM, Guan L, Wu Y, Lee JR, Kim SC, Kim YW and Zhao R: Isoliquiritigenin attenuates oxidative hepatic damage induced by carbon tetrachloride with or without buthionine sulfoximine. Chem Biol Interact. 225:13–20. 2015. View Article : Google Scholar : PubMed/NCBI
13	Yadav VR, Prasad S, Sung B and Aggarwal BB: The role of chalcones in suppression of NF-κB-mediated inflammation and cancer. Int Immunopharmacol. 11:295–309. 2011. View Article : Google Scholar : PubMed/NCBI
14	Chen XY, Li DF, Han JC, Wang B, Dong ZP, Yu LN, Pan ZH, Qu CJ, Chen Y, Sun SG and Zheng QS: Reprogramming induced by isoliquiritigenin diminishes melanoma cachexia through mTORC2-AKT-GSK3β signaling. Oncotarget. 8:34565–34575. 2017.PubMed/NCBI
15	Wang Z, Wang N, Liu P, Chen Q, Situ H, Xie T, Zhang J, Peng C, Lin Y and Chen J: MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. Oncotarget. 5:7013–7026. 2014.PubMed/NCBI
16	Zhao H, Yuan X, Li D, Chen H, Jiang J, Wang Z, Sun X and Zheng Q: Isoliquiritigen enhances the antitumour activity and decreases the genotoxic effect of cyclophosphamide. Molecules. 18:8786–8798. 2013. View Article : Google Scholar : PubMed/NCBI
17	Kim DH, Park JE, Chae IG, Park G, Lee S and Chun KS: Isoliquiritigenin inhibits the proliferation of human renal carcinoma Caki cells through the ROS-mediated regulation of the Jak2/STAT3 pathway. Oncol Rep. 38:575–583. 2017. View Article : Google Scholar : PubMed/NCBI
18	Yoshida T, Horinaka M, Takara M, Tsuchihashi M, Mukai N, Wakada M and Sakai T: Combination of isoliquiritigenin and tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis in colon cancer HT29 cells. Environ Health Prev Med. 13:281–287. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kwon GT, Cho HJ, Chung WY, Park KK, Moon A and Park JH: Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: Possible mediation by decreased JNK/AP-1 signaling. J Nutr Biochem. 20:663–676. 2009. View Article : Google Scholar : PubMed/NCBI
20	Hsia SM, Yu CC, Shih YH, Chen Yuanchien M, Wang TH, Huang YT and Shieh TM: Isoliquiritigenin as a cause of DNA damage and inhibitor of ataxia-telangiectasia mutated expression leading to G2/M phase arrest and apoptosis in oral squamous cell carcinoma. Head Neck. 38 Suppl 1:E360–E371. 2016. View Article : Google Scholar : PubMed/NCBI
21	Hsu YL, Chia CC, Chen PJ, Huang SE, Huang SC and Kuo PL: Shallot and licorice constituent isoliquiritigenin arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and initiation of the mitochondrial system in human cervical carcinoma HeLa cells. Mol Nutr Food Res. 53:826–835. 2009. View Article : Google Scholar : PubMed/NCBI
22	Ma J, Fu NY, Pang DB, Wu WY and Xu AL: Apoptosis induced by isoliquiritigenin in human gastric cancer MGC-803 cells. Planta Med. 67:754–757. 2001. View Article : Google Scholar : PubMed/NCBI
23	Lin M, Wu D and Huang Y: Natural compounds ursolic acid and isoliquiritigenin target GRP78 to enhance human gastric cancer cell chemosensitivity by 5-fluorouracil. FASEB J. 30:1193–1194. 2016.
24	Wu CH, Chen HY, Wang CW, Shieh TM, Huang TC, Lin LC, Wang KL and Hsia SM: Isoliquiritigenin induces apoptosis and autophagy and inhibits endometrial cancer growth in mice. Oncotarget. 7:73432–73447. 2016.PubMed/NCBI
25	Chen G, Zhu L, Liu Y, Zhou Q, Chen H and Yang J: Isoliquiritigenin, a flavonoid from licorice, plays a dual role in regulating gastrointestinal motility in vitro and in vivo. Phytother Res. 23:498–506. 2009. View Article : Google Scholar : PubMed/NCBI
26	Jergens A, Young J, Moore D, Wang C, Hostetter J, Augustine L, Allenspach K, Schmitz S and Mosher C: Bcl-2/caspase 3 mucosal imbalance favors T cell resistance to apoptosis in dogs with inflammatory bowel disease. Vet Immunol Immunopathol. 158:167–174. 2014. View Article : Google Scholar : PubMed/NCBI
27	Renault TT, Floros KV, Elkholi R, Corrigan KA, Kushnareva Y, Wieder SY, Lindtner C, Serasinghe MN, Asciolla JJ, Buettner C, et al: Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell. 57:69–82. 2015. View Article : Google Scholar : PubMed/NCBI
28	Fang H, Wu Y, Guo J, Rong J, Ma L, Zhao Z, Zuo D and Peng S: T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway. Apoptosis. 17:895–907. 2012. View Article : Google Scholar : PubMed/NCBI
29	Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, Geneste O and Kroemer G: BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy. 3:374–376. 2007. View Article : Google Scholar : PubMed/NCBI
30	Shvets E, Abada A, Weidberg H and Elazar Z: Dissecting the involvement of LC3B and GATE-16 in p62 recruitment into autophagosomes. Autophagy. 7:683–688. 2011. View Article : Google Scholar : PubMed/NCBI
31	Wei Y, An Z, Zou Z, Sumpter R, Su M, Zang X, Sinha S, Gaestel M and Levine B: The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation. elife. 4:e052892015. View Article : Google Scholar :
32	Wang Z, Wang N, Han S, Wang D, Mo S, Yu L, Huang H, Tsui K, Shen J and Chen J: Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLoS One. 8:e685662013. View Article : Google Scholar : PubMed/NCBI
33	Chen T, Deng S and Lin R: The inhibitory effect of Isoliquiritigenin on the proliferation of human arterial smooth muscle cell. BMC Pharmacol Toxicol. 18:572017. View Article : Google Scholar : PubMed/NCBI
34	Chen G, Hu X, Zhang W, Xu N, Wang FQ, Jia J, Zhang WF, Sun ZJ and Zhao YF: Mammalian target of rapamycin regulates isoliquiritigenin-induced autophagic and apoptotic cell death in adenoid cystic carcinoma cells. Apoptosis. 17:90–101. 2012. View Article : Google Scholar : PubMed/NCBI
35	Wu S, Xue J, Yang Y, Zhu H, Chen F, Wang J, Lou G, Liu Y, Shi Y, Yu Y, et al: Isoliquiritigenin inhibits interferon-γ-inducible genes expression in hepatocytes through down-regulating activation of JAK1/STAT1, IRF3/MyD88, ERK/MAPK, JNK/MAPK and PI3K/Akt signaling pathways. Cell Physiol Biochem. 37:501–514. 2015. View Article : Google Scholar : PubMed/NCBI
36	Safdari Y, Khalili M, Ebrahimzadeh MA, Yazdani Y and Farajnia S: Natural inhibitors of PI3K/AKT signaling in breast cancer: emphasis on newly-discovered molecular mechanisms of action. Pharmacol Res. 93:1–10. 2015. View Article : Google Scholar : PubMed/NCBI
37	Wang ZG, Wang Y, Huang Y, Lu Q, Zheng L, Hu D, Feng WK, Liu YL, Ji KT, Zhang HY, et al: bFGF regulates autophagy and ubiquitinated protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway. Sci Rep. 5:92872015. View Article : Google Scholar : PubMed/NCBI
38	Dillon RL, White DE and Muller WJ: The phosphatidyl inositol 3-kinase signaling network: Implications for human breast cancer. Oncogene. 26:1338–1345. 2007. View Article : Google Scholar : PubMed/NCBI
39	Chen L, Wang J, Wang B, Yang J, Gong Z, Zhao X, Zhang C and Du K: MiR-126 inhibits vascular endothelial cell apoptosis through targeting PI3K/Akt signaling. Ann Hematol. 95:365–374. 2016. View Article : Google Scholar : PubMed/NCBI
40	Arsham AM, Plas DR, Thompson CB and Simon MC: Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription. J Biol Chem. 277:15162–15170. 2002. View Article : Google Scholar : PubMed/NCBI
41	Sharma S, Guru SK, Manda S, Kumar A, Mintoo MJ, Prasad VD, Sharma PR, Mondhe DM, Bharate SB and Bhushan S: A marine sponge alkaloid derivative 4-chloro fascaplysin inhibits tumor growth and VEGF mediated angiogenesis by disrupting PI3K/Akt/mTOR signaling cascade. Chem Biol Interact. 275:47–60. 2017. View Article : Google Scholar : PubMed/NCBI
42	Cheng TC, Din ZH, Su JH, Wu YJ and Liu CI: sinulariolide suppresses cell migration and invasion by inhibiting matrix metalloproteinase-2/-9 and urokinase through the PI3K/AKT/mTOR signaling pathway in human bladder cancer cells. Mar Drugs. 15:pii: E238. 2017. View Article : Google Scholar
43	Capes-Davis A, Theodosopoulos G, Atkin I, Drexler HG, Kohara A, MacLeod RA, Masters JR, Nakamura Y, Reid YA, Reddel RR and Freshney RI: Check your cultures! A list of cross-contaminated or misidentified cell lines. Int J Cancer. 127:1–8. 2010. View Article : Google Scholar : PubMed/NCBI