Isoliquiritigenin inhibits cell proliferation and migration through the PI3K/AKT signaling pathway in A549 lung cancer cells

Tian,Tao; Sun,Jinpeng; Wang,Jianxin; Liu,Yanchun; Liu,Haitao

doi:10.3892/ol.2018.9344

Isoliquiritigenin inhibits cell proliferation and migration through the PI3K/AKT signaling pathway in A549 lung cancer cells

Authors:
- Tao Tian
- Jinpeng Sun
- Jianxin Wang
- Yanchun Liu
- Haitao Liu
View Affiliations

Affiliations: Department of Respiratory Medicine, Hebei Medical University Affiliated North China Petroleum Bureau General Hospital, Renqiu, Hebei 062552, P.R. China, Department of Surgical Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western of Hebei Province, Cangzhou, Hebei 061001, P.R. China
Published online on: August 21, 2018 https://doi.org/10.3892/ol.2018.9344
Pages: 6133-6139

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 molecular mechanisms of inhibition of Isoliquiritigenin (ISL) on the proliferation and migration of A549 cells. A549 cells were cultured in vitro, and the effects of ISL inhibition were examined using cell counting kit‑8, Transwell invasion and flow cytometric assays. Western blot analysis was also performed to detect cell apoptosis and the expression of phosphatidylinositol 3‑kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway‑associated proteins. The results demonstrated a significant inhibition of proliferation and migration of A549 cells when treated with ISL (P<0.05). Furthermore, ISL treatment significantly downregulated the expression of E‑cadherin, and upregulated the expression of N‑cadherin and vimentin. Flow cytometric analysis revealed a significant increase in cell apoptosis in the ISL group as well as the expression of pro‑apoptotic proteins Bcl‑2‑associated X protein and active caspase‑3. Conversely, the expression of anti‑apoptotic protein B‑cell lymphoma 2 was decreased. There was a significant decrease in the phosphorylation of AKT and mammalian target of rapamycin, and in the expression of cell proliferation proteins P70 and cyclin D1 in ISL‑treated cells. In conclusion, ISL has significant inhibitory effects on the proliferation and migration of A549 cells by promoting cell apoptosis. The mechanism may involve of PI3K/AKT signaling pathways in A549 cells, which may a potential therapeutic target for the treatment of lung cancer.

View Figures

View References

1	Hoffman PC, Mauer AM and Vokes EE: Lung cancer. Lancet. 355:479–485. 2000. View Article : Google Scholar : PubMed/NCBI
2	Bilello KS, Murin S and Matthay RA: Epidemiology, etiology, and prevention of lung cancer. Clin Chest Med. 23:1–25. 2002. View Article : Google Scholar : PubMed/NCBI
3	Sundar R, Soong R, Cho BC, Brahmer JR and Soo RA: Immunotherapy in the treatment of non-small cell lung cancer. Lung Cancer. 85:101–109. 2014. View Article : Google Scholar : PubMed/NCBI
4	Zhao J, Qiao CR, Ding Z, Sheng YL, Li XN, Yang Y, Zhu DY, Zhang CY, Liu DL, Wu K and Zhao S: A novel pathway in NSCLC cells: miR-191, targeting NFIA, is induced by chronic hypoxia, and promotes cell proliferation and migration. Mol Med Rep. 15:1319–1325. 2017. View Article : Google Scholar : PubMed/NCBI
5	Centers for Disease Control and Prevention (CDC), . Recent trends in mortality rates for four major cancers, by sex and race/ethnicity-united states, 1990–1998. MMWR Morb Mortal Wkly Rep. 51:49–53. 2002.PubMed/NCBI
6	Scott WJ, Howington J, Feigenberg S, Movsas B and Pisters K; American College of Chest Physicians, : Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 132 Suppl 3:S234–S242. 2007. View Article : Google Scholar
7	Rosell R and Karachaliou N: Lung cancer: Maintenance therapy and precision medicine in NSCLC. Nat Rev Clin Oncol. 10:549–550. 2013. View Article : Google Scholar : PubMed/NCBI
8	Sun SJ, Lin Q, Ma JX, Shi WW, Yang B and Li F: Long non-coding RNA NEAT1 acts as oncogene in NSCLC by regulating the Wnt signaling pathway. Eur Rev Med Pharmacol Sci. 21:504–510. 2017.PubMed/NCBI
9	Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R and Jemal A: Cancer treatment and survivorship statistics, 2016. Ca Cancer J Clin. 66:271–289. 2016. View Article : Google Scholar : PubMed/NCBI
10	Zhang Y, Li ZY, Hou XX, Wang X, Luo YH, Ying YP and Chen G: Clinical significance and effect of AEG-1 on the proliferation, invasion, and migration of NSCLC: A study based on immunohistochemistry, TCGA, bioinformatics, in vitro and in vivo verification. Oncotarget. 8:16531–16552. 2017.PubMed/NCBI
11	Vaya J, Belinky PA and Aviram M: Antioxidant constituents from licorice roots: Isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med. 23:302–313. 1997. View Article : Google Scholar : PubMed/NCBI
12	Chan SC, Chang YS, Wang JP, Chen SC and Kuo SC: Three new flavonoids and antiallergic, anti-inflammatory constituents from the heartwood of dalbergia odorifera. Planta Med. 64:153–158. 1998. View Article : Google Scholar : PubMed/NCBI
13	Yamamoto S, Aizu E, Jiang H, Nakadate T, Kiyoto I, Wang JC and Kato R: The potent anti-tumor-promoting agent isoliquiritigenin. Carcinogenesis. 12:317–323. 1991. View Article : Google Scholar : PubMed/NCBI
14	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
15	Kanazawa M, Satomi Y, Mizutani Y, Ukimura O, Kawauchi A, Sakai T, Baba M, Okuyama T, Nishino H and Miki T: Isoliquiritigenin inhibits the growth of prostate cancer. Eur Urol. 43:580–586. 2003. View Article : Google Scholar : PubMed/NCBI
16	Hsu YL, Kuo PL, Lin LT and Lin CC: Isoliquiritigenin inhibits cell proliferation and induces apoptosis in human hepatoma cells. Planta Med. 71:130–134. 2005. View Article : Google Scholar : PubMed/NCBI
17	Wang KL, Hsia SM, Chan CJ, Chang FY, Huang CY, Bau DT and Wang PS: Inhibitory effects of isoliquiritigenin on the migration and invasion of human breast cancer cells. Expert Opin Ther Targets. 17:337–349. 2013. View Article : Google Scholar : PubMed/NCBI
18	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
19	Hsu YL, Kuo PL, Chiang LC and Lin CC: Isoliquiritigenin inhibits the proliferation and induces the apoptosis of human non-small cell lung cancer a549 cells. Clin Exp Pharmacol Physiol. 31:414–418. 2004. View Article : Google Scholar : PubMed/NCBI
20	Cao LJ, Li HD, Yan M, Li ZH, Gong H, Jiang P, Deng Y, Fang PF and Zhang BK: The protective effects of isoliquiritigenin and glycyrrhetinic acid against triptolide-induced oxidative stress in hepG2 cells involve Nrf2 activation. Evid Based Complement Alternat Med. 2016:89121842016. View Article : Google Scholar : PubMed/NCBI
21	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
22	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
23	Li Y, Zhao H, Wang Y, Zheng H, Yu W, Chai H, Zhang J, Falck JR, Guo AM, Yue J, et al: Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. Toxicol Appl Pharmacol. 272:37–48. 2013. View Article : Google Scholar : PubMed/NCBI
24	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
25	Xu G, Zhang W, Bertram P, Zheng XF and Mcleod H: Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. Int J Oncol. 24:893–900. 2004.PubMed/NCBI
26	Zhou Y and Ho WS: Combination of liquiritin, isoliquiritin and isoliquirigenin induce apoptotic cell death through upregulating p53 and p21 in the A549 non-small cell lung cancer cells. Oncol Rep. 31:298–304. 2014. View Article : Google Scholar : PubMed/NCBI
27	Xiao C, Wu CH and Hu HZ: LncRNA UCA1 promotes epithelial-mesenchymal transition (EMT) of breast cancer cells via enhancing Wnt/beta-catenin signaling pathway. Eur Rev Med Pharmacol Sci. 20:2819–2824. 2016.PubMed/NCBI
28	Magnaldo T and Sarasin A: Xeroderma pigmentosum: From symptoms and genetics to gene-based skin therapy. Cells Tissues Organs. 177:189–198. 2004. View Article : Google Scholar : PubMed/NCBI
29	Meier P, Finch A and Evan G: Apoptosis in development. Nature. 407:796–801. 2000. View Article : Google Scholar : PubMed/NCBI
30	Kerr JF, Wyllie AH and Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 26:239–257. 1972. View Article : Google Scholar : PubMed/NCBI
31	Ola MS, Nawaz M and Ahsan H: Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 351:41–58. 2011. View Article : Google Scholar : PubMed/NCBI
32	Borner C: The Bcl-2 protein family: Sensors and checkpoints for life-or-death decisions. Mol Immunol. 39:615–647. 2003. View Article : Google Scholar : PubMed/NCBI
33	Brown R: The bcl-2 family of proteins. Br Med Bull. 53:466–477. 1997. View Article : Google Scholar : PubMed/NCBI
34	Zhao H, Yenari MA, Cheng D, Sapolsky RM and Steinberg GK: Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem. 85:1026–1036. 2003. View Article : Google Scholar : PubMed/NCBI
35	Zhou GS, Song LJ and Yang B: Isoliquiritigenin inhibits proliferation and induces apoptosis of U87 human glioma cells in vitro. Mol Med Rep. 7:531–536. 2013. View Article : Google Scholar : PubMed/NCBI
36	Jung JI, Chung E, Mi RS, Seon MR, Shin HK, Kim EJ, Lim SS, Chung WY, Park KK and Park JH: Isoliquiritigenin (ISL) inhibits ErbB3 signaling in prostate cancer cells. Biofactors. 28:159–168. 2006. View Article : Google Scholar : PubMed/NCBI
37	Kang SW, Choi JS, Choi YJ, Bae JY, Li J, Kim DS, Kim JL, Shin SY, Lee YJ, Kwun IS and Kang YH: Licorice isoliquiritigenin dampens angiogenic activity via inhibition of MAPK-responsive signaling pathways leading to induction of matrix metalloproteinases. J Nutr Biochem. 21:55–65. 2010. View Article : Google Scholar : PubMed/NCBI
38	Kim N, Jeong S, Jing K, Shin S, Kim S, Heo JY, Kweon GR, Park SK, Wu T, Park JI and Lim K: Docosahexaenoic acid induces cell death in human non-small cell lung cancer cells by repressing mTOR via AMPK activation and PI3K/akt inhibition. Biomed Res Int. 2015:2397642015.PubMed/NCBI
39	Li YC, He SM, He ZX, Li M, Yang Y, Pang JX, Zhang X, Chow K, Zhou Q, Duan W, et al: Plumbagin induces apoptotic and autophagic cell death through inhibition of the PI3K/Akt/mTOR pathway in human non-small cell lung cancer cells. Cancer Lett. 344:239–259. 2014. View Article : Google Scholar : PubMed/NCBI