Inhibition of cell proliferation and tumor growth of colorectal cancer by inhibitors of Wnt and Notch signaling pathways

Xiao,Yuliang; Yang,Xiaojing; Miao,Yinglei; He,Xikun; Wang,Ming; Sha,Weihong

doi:10.3892/ol.2016.5175

Inhibition of cell proliferation and tumor growth of colorectal cancer by inhibitors of Wnt and Notch signaling pathways

Authors:
- Yuliang Xiao
- Xiaojing Yang
- Yinglei Miao
- Xikun He
- Ming Wang
- Weihong Sha
View Affiliations

Affiliations: Department of Graduate School, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Foreign Language Department, Kunming Medical University, Kunming, Yunan 650032, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunan 650032, P.R. China, Department of Gastroenterology, The Second People's Hospital of Yunnan, Kunming, Yunan 650021, P.R. China, Department of Gastroenterology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
Published online on: September 22, 2016 https://doi.org/10.3892/ol.2016.5175
Pages: 3695-3700
Copyright: © Xiao 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

Understanding the role and mechanism of signaling pathways including Notch and Wnt in colorectal carcinogenesis is critical to the development of novel therapeutics. In the present study, we analyzed the cell proliferation, migration, G2/M percentage and the expression of molecules of signaling pathways in HCT‑116 cells through the inhibition of Wnt and Notch pathways, and also investigated the effect of inhibitors of Wnt and Notch pathways on tumor growth in a transplantation tumor model. We observed that rDDK‑1 (an inhibitor of the Wnt signaling pathway) and LY374973 (an inhibitor of the Notch signaling pathway) synergistically inhibited the proliferation, migration and G2/M percentage of HCT‑116 cell lines, and could further synergistically inhibit the tumor volume and weight in the transplantation tumor model. In the cell line and the transplantation tumor model, rDDK‑1 and LY374973 further synergistically inhibited the expression level of all detected Wnt and Notch pathway genes. Our results may pave the way for using inhibitors of Wnt and Notch signaling pathways together to treat colorectal cancer.

View Figures

View References

1	Curtin JC: Novel drug discovery opportunities for colorectal cancer. Expert Opin Drug Discov. 8:1153–1164. 2013. View Article : Google Scholar : PubMed/NCBI
2	Lei T, Chen WQ, Zhang SW, Lei TH, Ying Q, He ZY and Wang XH: Prevalence trend of colorectal cancer in 10 cities and counties in China from 1988 to 2002. Zhonghua Zhong Liu Za Zhi. 31:428–433. 2009.(In Chinese). PubMed/NCBI
3	Li HL, Gao YT, Zheng Y, Zhang W, Gao LF, Xu B and Xiang YB: Incidence trends of colorectal cancer in urban Shanghai, 1973-2005. Zhonghua Yu Fang Yi Xue Za Zhi. 43:875–879. 2009.(In Chinese). PubMed/NCBI
4	Bertrand FE, Angus CW, Partis WJ and Sigounas G: Developmental pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle. 11:4344–4351. 2012. View Article : Google Scholar : PubMed/NCBI
5	Wu WK, Wang XJ, Cheng AS, Luo MX, Ng SS, To KF, Chan FK, Cho CH, Sung JJ and Yu J: Dysregulation and crosstalk of cellular signaling pathways in colon carcinogenesis. Crit Rev Oncol Hematol. 86:251–277. 2013. View Article : Google Scholar : PubMed/NCBI
6	Saif MW and Chu E: Biology of colorectal cancer. Cancer J. 16:196–201. 2010. View Article : Google Scholar : PubMed/NCBI
7	Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, Johnson L and Reddy EP: Liver stem cells and hepatocellular carcinoma. Hepatology. 49:318–329. 2009. View Article : Google Scholar : PubMed/NCBI
8	Ischenko I, Seeliger H, Schaffer M, Jauch KW and Bruns CJ: Cancer stem cells: how can we target them? Curr Med Chem. 15:3171–3184. 2008. View Article : Google Scholar : PubMed/NCBI
9	Wang G, Brennan C, Rook M, Wolfe JL, Leo C, Chin L, Pan H, Liu WH, Price B and Makrigiorgos GM: Balanced-PCR amplification allows unbiased identification of genomic copy changes in minute cell and tissue samples. Nucleic Acids Res. 32:e762004. View Article : Google Scholar : PubMed/NCBI
10	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
11	Pope JL, Ahmad R, Bhat AA, Washington MK, Singh AB and Dhawan P: Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis. Mol Cancer. 13:1672014. View Article : Google Scholar : PubMed/NCBI
12	Umar S: Enteric pathogens and cellular transformation: bridging the gaps. Oncotarget. 5:6573–6575. 2014. View Article : Google Scholar : PubMed/NCBI
13	Gopalakrishnan N, Saravanakumar M, Madankumar P, Thiyagu M and Devaraj H: Colocalization of β-catenin with Notch intracellular domain in colon cancer: a possible role of Notch1 signaling in activation of CyclinD1-mediated cell proliferation. Mol Cell Biochem. 396:281–293. 2014. View Article : Google Scholar : PubMed/NCBI
14	Kwon C, Cheng P, King IN, Andersen P, Shenje L, Nigam V and Srivastava D: Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat Cell Biol. 13:1244–1251. 2011. View Article : Google Scholar : PubMed/NCBI
15	Bordonaro M, Tewari S, Atamna W and Lazarova DL: The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways. Exp Cell Res. 317:1368–1381. 2011. View Article : Google Scholar : PubMed/NCBI
16	Zhu J, Wang J, Shi Z, Franklin JL, Deane NG, Coffey RJ, Beauchamp RD and Zhang B: Deciphering genomic alterations in colorectal cancer through transcriptional subtype-based network analysis. PLoS One. 8:e792822013. View Article : Google Scholar : PubMed/NCBI
17	Prasetyanti PR, Zimberlin CD, Bots M, Vermeulen L, Fde S Melo and Medema JP: Regulation of stem cell self-renewal and differentiation by Wnt and Notch are conserved throughout the adenoma-carcinoma sequence in the colon. Mol Cancer. 12:1262013. View Article : Google Scholar : PubMed/NCBI
18	Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson BC, Lockwood G, Gallinger S and Egan SE: Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol. 33:1223–1229. 2008.PubMed/NCBI
19	Katoh M and Katoh M: Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med. 17:681–685. 2006.PubMed/NCBI
20	Korkaya H and Wicha MS: Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 21:299–310. 2007. View Article : Google Scholar : PubMed/NCBI
21	Karamboulas C and Ailles L: Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 1830:2481–2495. 2013. View Article : Google Scholar : PubMed/NCBI
22	Roy S and Majumdar AP: Signaling in colon cancer stem cells. J Mol Signal. 7:112012. View Article : Google Scholar : PubMed/NCBI
23	Pandurangan AK and Esa NM: Dietary non-nutritive factors in targeting of regulatory molecules in colorectal cancer: an update. Asian Pac J Cancer Prev. 14:5543–5552. 2013. View Article : Google Scholar : PubMed/NCBI
24	Singh BN, Shankar S and Srivastava RK: Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 82:1807–1821. 2011. View Article : Google Scholar : PubMed/NCBI