Open Access

Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial‑ mesenchymal transition via the AKT/GSK‑3β/Snail signaling pathway

  • Authors:
    • Li Yuan
    • Mengmeng Zhou
    • Dawei Huang
    • Harpreet S. Wasan
    • Kai Zhang
    • Leitao Sun
    • Hong Huang
    • Shenglin Ma
    • Minhe Shen
    • Shanming Ruan
  • View Affiliations

  • Published online on: July 25, 2019     https://doi.org/10.3892/mmr.2019.10528
  • Pages: 2783-2795
  • Copyright: © Yuan 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: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The identification of safe and effective drugs that inhibit tumor invasion and metastasis is required to improve the clinical outcome of patients with colon cancer. The present study aimed to investigate the inhibitory effects and possible mechanisms of action of resveratrol against the invasion and metastasis of colon cancer. AKT1‑knockdown SW480 and SW620 colon cancer cells were used to detect the effects of resveratrol on cell invasion and metastasis, as well as changes in the expression of epithelial‑mesenchymal transition (EMT) markers and serine/threonine kinase (AKT)/glycogen synthase kinase (GSK)‑3β/Snail signaling pathway‑related molecules in vitro. Furthermore, nude mice were inoculated with SW480 cells in the tail vein to establish an in vivo lung metastasis model of colon cancer, to investigate the effects of resveratrol on lung metastasis in colon cancer. The results revealed that resveratrol treatment and AKT1 knockdown significantly inhibited cell migration and invasion in colon cancer, and markedly increased E‑cadherin expression and decreased that of N‑cadherin, phospho (p)‑AKT1, p‑GSK‑3β, and Snail in colon cancer both in vitro and in vivo. Furthermore, the effects of resveratrol were significantly weaker in the AKT1‑knockdown cells. In conclusion, resveratrol may suppress the invasion and metastasis of colon cancer through reversal of EMT via the AKT/GSK‑3β/Snail signaling pathway. AKT1 may therefore be a key regulator of EMT in colon cancer cells and a potential therapeutic target for this disease.

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 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A and Jemal A: Colorectal cancer statistics, 2017. CA Cancer J Clin. 67:177–193. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan DC, Zhang JF and Waye MM: The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget. 6:22513–22525. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, Jemal A, Schymura MJ, Lansdorp-Vogelaar I, Seeff LC, et al: Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 116:544–573. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Diepenbruck M and Christofori G: Epithelial-mesenchymal transition (EMT) and metastasis: Yes, no, maybe? Curr Opin Cell Biol. 43:7–13. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Vences-Catalan F and Levy S: Immune targeting of tetraspanins involved in cell invasion and metastasis. Front Immunol. 9:12772018. View Article : Google Scholar : PubMed/NCBI

9 

Carter LG, D'Orazio JA and Pearson KJ: Resveratrol and cancer: Focus on in vivo evidence. Endocr Relat Cancer. 21:R209–R225. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Borriello A: Resveratrol in cancer prevention and treatment: Focusing on molecular targets and mechanism of action. Proceedings. 1:9762017. View Article : Google Scholar

11 

Kim SE, Shin SH, Lee JY, Kim CH, Chung IK, Kang HM, Park HR, Park BS and Kim IR: Resveratrol induces mitochondrial apoptosis and inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma cells. Nutr Cancer. 70:125–135. 2018. View Article : Google Scholar : PubMed/NCBI

12 

Cilibrasi C, Riva G, Romano G, Cadamuro M, Bazzoni R, Butta V, Paoletta L, Dalprà L, Strazzabosco M, Lavitrano M, et al: Resveratrol impairs glioma stem cells proliferation and motility by modulating the wnt signaling pathway. PLoS One. 12:e01698542017. View Article : Google Scholar : PubMed/NCBI

13 

Li W, Ma J, Ma Q, Li B, Han L, Liu J, Xu Q, Duan W, Yu S, Wang F and Wu E: Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. Curr Med Chem. 20:4185–4194. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Aiello NM, Maddipati R, Norgard RJ, Balli D, Li J, Yuan S, Yamazoe T, Black T, Sahmoud A, Furth EE, et al: EMT subtype influences epithelial plasticity and mode of cell migration. Dev Cell. 45:681–695.e684. 2018. View Article : Google Scholar : PubMed/NCBI

15 

Zhang H, Sun JD, Yan LJ and Zhao XP: PDGF-D/PDGFRβ promotes tongue squamous carcinoma cell (TSCC) progression via activating p38/AKT/ERK/EMT signal pathway. Biochem Biophys Res Commun. 478:845–851. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Saegusa M, Hashimura M, Kuwata T and Okayasu I: Requirement of the Akt/beta-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug. Am J Pathol. 174:2107–2115. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Tokunaga E, Oki E, Egashira A, Sadanaga N, Morita M, Kakeji Y and Maehara Y: Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets. 8:27–36. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Dou Y, Lei JQ, Guo SL, Zhao D, Yue HM and Yu Q: The CNPY2 enhances epithelial-mesenchymal transition via activating the AKT/GSK3β pathway in non-small cell lung cancer. Cell Biol Int. 42:959–964. 2018. View Article : Google Scholar : PubMed/NCBI

19 

Lu LL, Chen XH, Zhang G, Liu ZC, Wu N, Wang H, Qi YF, Wang HS, Cai SH and Du J: CCL21 facilitates chemoresistance and cancer stem cell-like properties of colorectal cancer cells through AKT/GSK-3β/snail signals. Oxid Med Cell Longev. 2016:58741272016. View Article : Google Scholar : PubMed/NCBI

20 

Jiang H, Zhou Z, Jin S, Xu K, Zhang H and Xu J, Sun Q, Wang J and Xu J: PRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK-3β/Snail signaling. Cancer Sci. 109:1414–1427. 2018. View Article : Google Scholar : PubMed/NCBI

21 

Matsumoto T, Yokoi A, Hashimura M, Oguri Y, Akiya M and Saegusa M: TGF-β-mediated LEFTY/Akt/GSK-3β/Snail axis modulates epithelial-mesenchymal transition and cancer stem cell properties in ovarian clear cell carcinomas. Mol Carcinog. 57:957–967. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Li Y, Lin Z, Chen B, Chen S, Jiang Z, Zhou T, Hou Z and Wang Y: Ezrin/NF-kB activation regulates epithelial- mesenchymal transition induced by EGF and promotes metastasis of colorectal cancer. Biomed Pharmacother. 92:140–148. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Liu ZC, Chen XH, Song HX, Wang HS, Zhang G, Wang H, Chen DY, Fang R, Liu H, Cai SH and Du J: Snail regulated by PKC/GSK-3β pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res. 358:491–502. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

25 

Shimaoka H, Takeno S, Maki K, Sasaki T, Hasegawa S and Yamashita Y: A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer. Oncol Lett. 14:3019–3027. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Mateo-Lozano S, Bazzocco S, Rodrigues P, Mazzolini R, Andretta E, Dopeso H, Fernández Y, Del Llano E, Bilic J, Suárez-López L, et al: Loss of the EPH receptor B6 contributes to colorectal cancer metastasis. Sci Rep. 7:437022017. View Article : Google Scholar : PubMed/NCBI

27 

Liu X, Ji Q, Deng W, Chai N, Feng Y, Zhou L, Sui H, Li C, Sun X and Li Q: JianPi JieDu recipe inhibits epithelial-to-mesenchymal transition in colorectal cancer through TGF-β/Smad mediated Snail/E-cadherin expression. Biomed Res Int. 2017:26131982017.PubMed/NCBI

28 

Zhang Z, Chen H, Xu C, Song L, Huang L, Lai Y, Wang Y, Chen H, Gu D, Ren L and Yao Q: Curcumin inhibits tumor epithelialmesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells. Oncol Rep. 35:2615–2623. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Berman AY, Motechin RA, Wiesenfeld MY and Holz MK: The therapeutic potential of resveratrol: A review of clinical trials. NPJ Precis Oncol. 1:352017. View Article : Google Scholar : PubMed/NCBI

30 

Gao Q, Yuan Y, Gan HZ and Peng Q: Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis. Oncol Lett. 9:2381–2387. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Jiao Y, Li H, Liu Y, Guo A, Xu X, Qu X, Wang S, Zhao J, Li Y and Cao Y: Resveratrol inhibits the invasion of glioblastoma-initiating cells via down-regulation of the PI3K/Akt/NF-κB signaling pathway. Nutrients. 7:4383–4402. 2015. View Article : Google Scholar : PubMed/NCBI

32 

Kim YS, Sull JW and Sung HJ: Suppressing effect of resveratrol on the migration and invasion of human metastatic lung and cervical cancer cells. Mol Biol Rep. 39:8709–8716. 2012. View Article : Google Scholar : PubMed/NCBI

33 

Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, Sun J, Cai J, Qin J, Ren J and Li Q: Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-catenin signal pathway. Plos One. 8:e787002013. View Article : Google Scholar : PubMed/NCBI

34 

Ombrato L and Malanchi I: The EMT universe: Space between cancer cell dissemination and metastasis initiation. Crit Rev Oncog. 19:349–361. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Karimi Dermani F, Saidijam M, Amini R, Mahdavinezhad A, Heydari K and Najafi R: Resveratrol inhibits proliferation, invasion, and epithelial-mesenchymal transition by increasing miR-200c expression in HCT-116 colorectal cancer cells. J Cell Biochem. 118:1547–1555. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Buhrmann C, Shayan P, Kraehe P, Popper B, Goel A and Shakibaei M: Resveratrol induces chemosensitization to 5-fluorouracil through up-regulation of intercellular junctions, Epithelial-to-mesenchymal transition and apoptosis in colorectal cancer. Biochem Pharmacol. 98:51–68. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Ye X and Weinberg RA: Epithelial-mesenchymal plasticity: A central regulator of cancer progression. Trends Cell Biol. 25:675–686. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Zhang X, Jiang G, Sun M, Zhou H, Miao Y, Liang M, Wang E and Zhang Y: Cytosolic THUMPD1 promotes breast cancer cells invasion and metastasis via the AKT-GSK3-Snail pathway. Oncotarget. 8:13357–13366. 2017.PubMed/NCBI

39 

Zhao J, Ou B, Han D, Wang P, Zong Y, Zhu C, Liu D, Zheng M, Sun J, Feng H and Lu A: Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer. 16:702017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yuan, L., Zhou, M., Huang, D., Wasan, H.S., Zhang, K., Sun, L. ... Ruan, S. (2019). Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial‑ mesenchymal transition via the AKT/GSK‑3β/Snail signaling pathway. Molecular Medicine Reports, 20, 2783-2795. https://doi.org/10.3892/mmr.2019.10528
MLA
Yuan, L., Zhou, M., Huang, D., Wasan, H. S., Zhang, K., Sun, L., Huang, H., Ma, S., Shen, M., Ruan, S."Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial‑ mesenchymal transition via the AKT/GSK‑3β/Snail signaling pathway". Molecular Medicine Reports 20.3 (2019): 2783-2795.
Chicago
Yuan, L., Zhou, M., Huang, D., Wasan, H. S., Zhang, K., Sun, L., Huang, H., Ma, S., Shen, M., Ruan, S."Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial‑ mesenchymal transition via the AKT/GSK‑3β/Snail signaling pathway". Molecular Medicine Reports 20, no. 3 (2019): 2783-2795. https://doi.org/10.3892/mmr.2019.10528