Ellagic acid induces cell cycle arrest and apoptosis via the TGF‑β1/Smad3 signaling pathway in human colon cancer HCT‑116 cells

Zhao,Jinlu; Li,Guodong; Wei,Jiufeng; Dang,Shuwei; Yu,Xiaotong; Ding,Lixian; Shang,Changquan; Zhang,Haopeng; Zhang,Zhicheng; Chen,Hongsheng; Liu,Ming

doi:10.3892/or.2020.7617

Ellagic acid induces cell cycle arrest and apoptosis via the TGF‑β1/Smad3 signaling pathway in human colon cancer HCT‑116 cells

Authors:
- Jinlu Zhao
- Guodong Li
- Jiufeng Wei
- Shuwei Dang
- Xiaotong Yu
- Lixian Ding
- Changquan Shang
- Haopeng Zhang
- Zhicheng Zhang
- Hongsheng Chen
- Ming Liu
View Affiliations

Affiliations: Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: May 20, 2020 https://doi.org/10.3892/or.2020.7617
Pages: 768-776

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

Colorectal carcinoma (CRC) is a major type of malignancy worldwide. Ellagic acid (EA), a natural phenolic constituent, has been shown to exhibit anticancer effects. In our previous study, it was shown that EA inhibited proliferation of CRC cells. Additionally, microarray analysis revealed 4,738 differentially expressed genes (DEGs) which were associated with multiple cellular events, including cell growth, apoptosis and angiogenesis. However, the associated pathways had not been validated. In the present study, it was shown that EA induced G0/G1 cell cycle arrest in HCT‑116 cells, and increased apoptosis. Furthermore, DEGs identified by cDNA microarray analysis were investigated, and showed changes in five genes which were associated with the TGF‑β1/Smad3 signaling pathway. TGF‑β1 small interfering RNA and SIS3, a Smad3 inhibitor, were used to assess the role of TGF‑β1 and Smad3, respectively, and it was shown that the they reduced the effects of EA on HCT‑116 CRC cells. In addition, the expression patterns of downstream DEGs of the TGF‑β1/Smad3 pathway were altered. Thus, this pathway may underlie the molecular mechanism by which EA exhibits its effects in vitro in CRC cells. Accordingly, targeting the TGF‑β1/Smad3 pathway with anticancer agents such as EA may be potentially used to treat CRC.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Jermal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar : PubMed/NCBI
3	Wu Q, Hu T, Zheng E, Deng X and Wang Z: Prognostic role of the lymphocyte-to-monocyte ratio in colorectal cancer: An up-to-date meta-analysis. Medicine (Baltimore). 96:e70512017. View Article : Google Scholar : PubMed/NCBI
4	Cragg GM and Newman DJ: Plants as a source of anti-cancer agents. J Ethnopharmacol. 100:72–79. 2005. View Article : Google Scholar : PubMed/NCBI
5	Whitley AC, Stoner GD, Darby MV and Walle T: Intestinal epithelial cell accumulation of the cancer preventive polyphenol Ellagic acid-extensive binding to protein and DNA. Biochem. Pharmacol. 66:907–915. 2003.
6	Aiyer HS, Vadhanam MV, Stoyanova R, Caprio GD, Clapper ML and Gupta RC: Dietary berries and Ellagic acid prevent oxidative DNA damage and modulate expression of DNA repair genes. Int J Mol Sci. 9:327–341. 2008. View Article : Google Scholar : PubMed/NCBI
7	Cho H, Jung H, Lee H, Yi HC, Kwak HK and Hwang KT: Chemopreventive activity of ellagitannins and their derivatives from black raspberry seeds on HT-29 colon cancer cells. Food Funct. 6:28612015. View Article : Google Scholar : PubMed/NCBI
8	Mertens-Talcott SU, Lee JH, Percival SS and Talcott ST: Induction of cell death in Caco-2 human colon carcinoma cells by Ellagic acid rich fractions from muscadine grapes. J Agric Food Chem. 54:5336–5343. 2006. View Article : Google Scholar : PubMed/NCBI
9	Li LW, Na C, Tian SY, Chen J, Ma R, Gao Y and Lou G: Ellagic acid induces HeLa cell apoptosis via regulating signal transducer and activator of transcription 3 signaling. Exp Ther Med. 16:29–36. 2018.PubMed/NCBI
10	Zhao JL, Li GD, Bo WL, Zhou YH, Dang SW, Wei JF, Li XL and Liu M: Multiple effects of Ellagic acid on human colorectal carcinoma cells identified by gene expression profile analysis. Int J oncol. 50:613–621. 2017. View Article : Google Scholar : PubMed/NCBI
11	Chen HS, Bai MH, Zhang T, Li GD and Liu M: Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol. 46:1730–1738. 2015. View Article : Google Scholar : PubMed/NCBI
12	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
13	Sung JJ, Lau JY, Young GP, Sano Y, Chiu HM, Byeon JS, Yeoh KG, Goh KL, Sollano J, Rerknimitr R, et al: Asia Pacific consensus recommendations for colorectal cancer screening. Gut. 57:1166–1176. 2008. View Article : Google Scholar : PubMed/NCBI
14	Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, Gavin A, Visser O and Bray F: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur. J Cancer. 103:356–387. 2018.
15	Ceci C, Lacal PM, Tentori L, De Martino MG, Miano R and Graziani G: Experimental Evidence of the antitumor, antimetastatic and antiangiogenic activity of Ellagic acid. Nutrients. 10(pii): E17562018. View Article : Google Scholar : PubMed/NCBI
16	Umesalma S and Sudhandiran G: Differential inhibitory effects of the polyphenol Ellagic acid on inflammatory mediators NF-kappaB, iNOS, COX-2, TNF-alpha, and IL-6 in 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Basic Clin Pharmacol Toxicol. 107:650–655. 2010. View Article : Google Scholar : PubMed/NCBI
17	Kong X, Ding X and Yang Q: Identification of multi-target effects of Huaier aqueous extract via microarray profling in triple-negative breast cancer cells. Int J Oncol. 46:2047–2056. 2015. View Article : Google Scholar : PubMed/NCBI
18	Heldin CH, Miyazono K and ten Dijke P: TGF-beta signaling from cell membrane to nucleus through SMAD proteins. Nature. 390:465–471. 1997. View Article : Google Scholar : PubMed/NCBI
19	Blobe GC, Schiemann WP and Lodish HF: Role of transforming growth factor beta in human disease. N Engl J Med. 342:1350–1358. 2000. View Article : Google Scholar : PubMed/NCBI
20	Siegel PM and Massagué J: Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 3:807–821. 2003. View Article : Google Scholar : PubMed/NCBI
21	Pardali K and Moustakas A: Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 1775:21–62. 2007.PubMed/NCBI
22	Ikushima H and Miyazono K: TGFbeta signaling: A complex web in cancer progression. Nat Rev Cancer. 10:415–424. 2010. View Article : Google Scholar : PubMed/NCBI
23	Zhang T, Chen HS, Wang LF, Bai MH, Wang YC, Jiang XF and Liu M: Ellagic acid exerts anti-proliferation effects via modulation of TGF-β/Smad3 signaling in MCF-7 breast cancer cells. Asian Pac J Cancer Prev. 15:273–276. 2014. View Article : Google Scholar : PubMed/NCBI
24	Zhou X, Suzuki H, Shimada Y, Imamura M, Yin J, Jiang HY, Tarmin L, Abraham JM and Meltzer S: Genomic DNA and messenger RNA expression alterations of the CDKN2B and CDKN2 genes in esophageal squamous carcinoma cell lines. Genes Chromosomes Cancer. 13:285–290. 1995. View Article : Google Scholar : PubMed/NCBI
25	Hannon G and Beach D: p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 371:257–261. 1994. View Article : Google Scholar : PubMed/NCBI
26	Musgrove EA, Lilischkis R, Cornish AL, Lee CS, Setlur V, Seshadri R and Sutherland RL: Expression of the Cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer. Int J Cancer. 63:584–591. 1995. View Article : Google Scholar : PubMed/NCBI
27	Erickson S, Sangfelt O, Heyman M, Castro J, Einhorn S and Grandér D: Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence. Oncogene. 17:595–602. 1998. View Article : Google Scholar : PubMed/NCBI
28	McNeal AS, Liu K, Nakhate V, Natale CA, Duperret EK, Capell BC, Dentchev T, Berger SL, Herlyn M, Seykora JT and Ridky TW: CDKN2B loss promotes progression from benign melanocytic nevus to melanoma. Cancer Discov. 5:1072–1085. 2015. View Article : Google Scholar : PubMed/NCBI
29	Malumbres M and Barbacid M: Mammalian cyclin-dependent kinases. Trends Biochem. Sci. 30:630–641. 2005.
30	Tsai JH, Hsu LS, Huang HC, Lin CL, Pan MH, Hong HM and Chen WJ: 1-(2-Hydroxy-5-methylphenyl)-3-phenyl-1, 3-propanedione Induces G1 cell cycle arrest and autophagy in HeLa cervical cancer cells. Int J Mol Sci. 17(pii): E12742016. View Article : Google Scholar : PubMed/NCBI
31	Derynck R, Zhang Y and Feng XH: Smads: Transcriptional activators of TGF-beta responses. Cell. 95:737–740. 1998. View Article : Google Scholar : PubMed/NCBI
32	Miyazono K, ten Dijke P and Heldin CH: TGF-beta signaling by Smad proteins. Adv Immunol. 75:115–157. 2000. View Article : Google Scholar : PubMed/NCBI