Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3β/β-catenin pathway

Wang,Ge; Feng,Cheng-Cheng; Chu,Shao-Jun; Zhang,Rui; Lu,Yun-Min; Zhu,Jin-Shui; Zhang,Jing

doi:10.3892/ijo.2015.3157

Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3β/β-catenin pathway

Authors:
- Ge Wang
- Cheng-Cheng Feng
- Shao-Jun Chu
- Rui Zhang
- Yun-Min Lu
- Jin-Shui Zhu
- Jing Zhang
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Affiliations: Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China, Department of Medicine, Rudong Hospital of Traditional Chinese Medicine, Nantong, Jiangsu 226400, P.R. China
Published online on: September 11, 2015 https://doi.org/10.3892/ijo.2015.3157
Pages: 1767-1774

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Abstract

AKT/GSK-3β/β-catenin signaling pathway plays an important role in the progression of colorectal cancer (CRC). Toosendanin (TSN) is a triterpenoid extracted from the bark or fruits of Melia toosendan Sieb et Zucc and possesses antitumour effects on various human cancer cells. However, its effect on CRC remains poorly understood. The present study investigated the effect of TSN on CRC SW480 cells and the AKT/GSK-3β/β-catenin signaling. Proliferation assay, flow cytometry and Hoechst 33342 nuclear staining demonstrated TSN dose-dependently inhibited cell viability and induced cell apoptosis as well as cell cycle arrest in S phase. Confocal laser scanning microscope showed β-catenin transferred to the outside of the nucleus in TSN-treated cells. Quantitative real-time PCR and western blot analysis found that TSN effectively modulated molecules related to apoptosis and AKT/GSK-3β/β‑catenin signaling. Moreover, TSN administration significantly inhibited CRC growth in a mouse tumor xenograft model. In conclusion, our findings indicate that TSN inhibits growth and induces apoptosis in CRC cells through suppression of AKT/GSK-3β/β-catenin pathway, suggesting that TSN may have potential for use in CRC treatment.

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1	Siegel R, Desantis C and Jemal A: Colorectal cancer statistics, 2014. CA Cancer J Clin. 64:104–117. 2014. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
3	Grady WM and Carethers JM: Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 135:1079–1099. 2008. View Article : Google Scholar : PubMed/NCBI
4	Kim KY, Cha IH, Ahn JB, Kim NK, Rha SY, Chung HC, Roh JK and Shin SJ: Estimating the adjuvant chemotherapy effect in elderly stage II and III colon cancer patients in an observational study. J Surg Oncol. 107:613–618. 2013. View Article : Google Scholar : PubMed/NCBI
5	Kolligs FT, Bommer G and Göke B: Wnt/beta-catenin/tcf signaling: A critical pathway in gastrointestinal tumorigenesis. Digestion. 66:131–144. 2002. View Article : Google Scholar : PubMed/NCBI
6	Gupta N, Schmitt F, Grebhardt S and Mayer D: Beta-catenin is a positive regulator of estrogen receptor-alpha function in breast cancer cells. Cancers (Basel). 3:2990–3001. 2011. View Article : Google Scholar
7	Yuan G, Wang C, Ma C, Chen N, Tian Q, Zhang T and Fu W: Oncogenic function of DACT1 in colon cancer through the regulation of β-catenin. PLoS One. 7:e340042012. View Article : Google Scholar
8	Satow R, Shitashige M, Jigami T, Fukami K, Honda K, Kitabayashi I and Yamada T: β-catenin inhibits promyelocytic leukemia protein tumor suppressor function in colorectal cancer cells. Gastroenterology. 142:572–581. 2012. View Article : Google Scholar
9	Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, Bicknell D, Bodmer WF and Tomlinson IP: APC mutations in sporadic colorectal tumors: A mutational ‘hotspot’ and interdependence of the ‘two hits’. Proc Natl Acad Sci USA. 97:3352–3357. 2000. View Article : Google Scholar
10	Angers S and Moon RT: Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 10:468–477. 2009.PubMed/NCBI
11	Mills CN, Nowsheen S, Bonner JA and Yang ES: Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors. Front Mol Neurosci. 4:472011. View Article : Google Scholar
12	Cohen P and Goedert M: GSK3 inhibitors: Development and therapeutic potential. Nat Rev Drug Discov. 3:479–487. 2004. View Article : Google Scholar : PubMed/NCBI
13	Cross DA, Alessi DR, Cohen P, Andjelkovich M and Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 378:785–789. 1995. View Article : Google Scholar : PubMed/NCBI
14	He Y, Wang J, Liu X, Zhang L, Yi G, Li C, He X, Wang P and Jiang H: Toosendanin inhibits hepatocellular carcinoma cells by inducing mitochondria-dependent apoptosis. Planta Med. 76:1447–1453. 2010. View Article : Google Scholar : PubMed/NCBI
15	Tang MZ, Wang ZF and Shi YL: Involvement of cytochrome c release and caspase activation in toosendanin-induced PC12 cell apoptosis. Toxicology. 201:31–38. 2004. View Article : Google Scholar : PubMed/NCBI
16	Yu JC, Min ZD and Ip NY: Melia toosendan regulates PC12 Cell differentiation via the activation of protein kinase A and extracellular signal-regulated kinases. Neurosignals. 13:248–257. 2004. View Article : Google Scholar : PubMed/NCBI
17	Zhang B, Wang ZF, Tang MZ and Shi YL: Growth inhibition and apoptosis-induced effect on human cancer cells of toosendanin, a triterpenoid derivative from chinese traditional medicine. Invest New Drugs. 23:547–553. 2005. View Article : Google Scholar : PubMed/NCBI
18	Clardy J and Walsh C: Lessons from natural molecules. Nature. 432:829–837. 2004. View Article : Google Scholar : PubMed/NCBI
19	Mishra BB and Tiwari VK: Natural products: An evolving role in future drug discovery. Eur J Med Chem. 46:4769–4807. 2011. View Article : Google Scholar : PubMed/NCBI
20	Ju J, Qi Z, Cai X, Cao P, Huang Y, Wang S, Liu N and Chen Y: The apoptotic effects of toosendanin are partially mediated by activation of deoxycytidine kinase in HL-60 cells. PLoS One. 7:e525362012. View Article : Google Scholar
21	Shi YL and Li MF: Biological effects of toosendanin, a triterpenoid extracted from Chinese traditional medicine. Prog Neurobiol. 82:1–10. 2007. View Article : Google Scholar : PubMed/NCBI
22	Tamgue O, Chai CS, Hao L, Zambe JC, Huang WW, Zhang B, Lei M and Wei YM: Triptolide inhibits histone methyltransferase EZH2 and modulates the expression of its target genes in prostate cancer cells. Asian Pac J Cancer Prev. 14:5663–5669. 2013. View Article : Google Scholar : PubMed/NCBI
23	Ji AJ, Liu SL, Ju WZ and Huang XE: Anti-proliferation effects and molecular mechanisms of action of tetramethypyrazine on human SGC-7901 gastric carcinoma cells. Asian Pac J Cancer Prev. 15:3581–3586. 2014. View Article : Google Scholar : PubMed/NCBI
24	Song YA, Park YL, Kim KY, Myung E, Chung CY, Cho SB, Lee WS, Jung YD, Kweon SS and Joo YE: RON is associated with tumor progression via the inhibition of apoptosis and cell cycle arrest in human gastric cancer. Pathol Int. 62:127–136. 2012. View Article : Google Scholar : PubMed/NCBI
25	Arends MJ, Morris RG and Wyllie AH: Apoptosis. The role of the endonuclease. Am J Pathol. 136:593–608. 1990.PubMed/NCBI
26	Porter AG and Jänicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6:99–104. 1999. View Article : Google Scholar : PubMed/NCBI
27	Gambi N, Tramontano F and Quesada P: Poly(ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines. Biochem Pharmacol. 75:2356–2363. 2008. View Article : Google Scholar : PubMed/NCBI
28	Burlacu A: Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med. 7:249–257. 2003. View Article : Google Scholar : PubMed/NCBI
29	Lu W, Jia G, Meng X, Zhao C, Zhang L, Ren Y, Pan H and Ni Y: Beta-catenin mediates the apoptosis induction effect of celastrol in HT29 cells. Life Sci. 91:279–283. 2012. View Article : Google Scholar : PubMed/NCBI
30	Li J and Zhou BP: Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer. 11:492011. View Article : Google Scholar
31	Cai C and Zhu X: The Wnt/β-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer. Mol Med Rep. 5:1191–1196. 2012.PubMed/NCBI
32	Nuñez F, Bravo S, Cruzat F, Montecino M and De Ferrari GV: Wnt/β-catenin signaling enhances cyclooxygenase-2 (COX2) transcriptional activity in gastric cancer cells. PLoS One. 6:e185622011. View Article : Google Scholar
33	Park EJ, Chung HJ, Park HJ, Kim GD, Ahn YH and Lee SK: Suppression of Src/ERK and GSK-3/β-catenin signaling by pinosylvin inhibits the growth of human colorectal cancer cells. Food Chem Toxicol. 55:424–433. 2013. View Article : Google Scholar : PubMed/NCBI
34	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
35	Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, et al: Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proc Natl Acad Sci USA. 94:6939–6942. 1997. View Article : Google Scholar : PubMed/NCBI
36	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
37	Li Q, Dashwood WM, Zhong X, Nakagama H and Dashwood RH: Bcl-2 overexpression in PhIP-induced colon tumors: Cloning of the rat Bcl-2 promoter and characterization of a pathway involving beta-catenin, c-Myc and E2F1. Oncogene. 26:6194–6202. 2007. View Article : Google Scholar : PubMed/NCBI