Ethoxysanguinarine inhibits viability and induces apoptosis of colorectal cancer cells by inhibiting CIP2A

Jin,Lan; Si,Yuan; Hong,Xing; Liu,Pengfei; Zhu,Beibei; Yu,Huiliang; Zhao,Xinhua; Qin,Shanshan; Xiong,Mengyuan; Liu,Ying; Luo,Zhiguo; Guo,Yang

doi:10.3892/ijo.2018.4323

Ethoxysanguinarine inhibits viability and induces apoptosis of colorectal cancer cells by inhibiting CIP2A

Authors:
- Lan Jin
- Yuan Si
- Xing Hong
- Pengfei Liu
- Beibei Zhu
- Huiliang Yu
- Xinhua Zhao
- Shanshan Qin
- Mengyuan Xiong
- Ying Liu
- Zhiguo Luo
- Yang Guo
View Affiliations

Affiliations: Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Hubei Province Key Laboratory of Conservation Biology for Shennongjia Golden Monkey, Administration of Shennongjia National Park, Shennongjia Forestry Region, Hubei 442421, P.R. China, Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
Published online on: March 16, 2018 https://doi.org/10.3892/ijo.2018.4323
Pages: 1569-1578

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

Cancerous inhibitor of protein phosphatase 2A (CIP2A) an endogenous inhibitor of protein phosphatase 2A (PP2A), which can promote proliferation and transformation of several cancer types, has been shown to be a target for tumor therapy. The present study investigated the effects and underlying mechanisms of action of a novel natural compound, ethoxysanguinarine (Eth), on colorectal cancer (CRC) cells. MTT assay and flow cytometric assay found that Eth inhibited the viability and induced the apoptosis of the CRC cells. The inhibition of viability and activation of apoptosis was mediated through the Eth-induced decrease in CIP2A expression. Knockdown of CIP2A by RNA interference sensitized, whereas overexpression of CIP2A antagonized, Eth-induced viability inhibition and apoptosis. Furthermore, western blot analysis suggested that Eth inhibited phosphorylation of CIP2A downstream molecule protein kinase B via the activation of PP2A. CRC xenograft tests also confirmed the antitumor effect of Eth in vivo. These results advance our understanding of Eth-induced viability inhibition and apoptosis, implying the requirement for further investigation of Eth as a CIP2A inhibitor for cancer therapies.

View Figures

View 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	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Center MM, DeSantis C and Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19:1893–1907. 2010. View Article : Google Scholar : PubMed/NCBI
4	Jonas S, Thelen A, Benckert C, Spinelli A, Sammain S, Neumann U, Rudolph B and Neuhaus P: Extended resections of liver metastases from colorectal cancer. World J Surg. 31:511–521. 2007. View Article : Google Scholar : PubMed/NCBI
5	Pericàs JM, Corredoira J and Miró JM; Hospital Clínic-Lucus Augusti Working Group for endocarditis: Colorectal adenomas. N Engl J Med. 375:387–388. 2016. View Article : Google Scholar : PubMed/NCBI
6	Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, et al: CIP2A inhibits PP2A in human malignancies. Cell. 130:51–62. 2007. View Article : Google Scholar : PubMed/NCBI
7	Li W, Ge Z, Liu C, Liu Z, Björkholm M, Jia J and Xu D: CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res. 14:3722–3728. 2008. View Article : Google Scholar : PubMed/NCBI
8	Ren J, Li W, Yan L, Jiao W, Tian S, Li D, Tang Y, Gu G, Liu H and Xu Z: Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients' survival. Br J Cancer. 105:1905–1911. 2011. View Article : Google Scholar : PubMed/NCBI
9	Liu CY, Shiau CW, Kuo HY, Huang HP, Chen MH, Tzeng CH and Chen KF: Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells. Haematologica. 98:729–738. 2013. View Article : Google Scholar :
10	Cai F, Zhang L, Xiao X, Duan C, Huang Q, Fan C, Li J, Liu X, Li S and Liu Y: Cucurbitacin B reverses multidrug resistance by targeting CIP2A to reactivate protein phosphatase 2A in MCF-7/adriamycin cells. Oncol Rep. 36:1180–1186. 2016. View Article : Google Scholar : PubMed/NCBI
11	Perrotti D and Neviani P: Protein phosphatase 2A: A target for anticancer therapy. Lancet Oncol. 14:e229–e238. 2013. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Ma L, Wen ZS, Cheng YX and Zhou GB: Ethoxysanguinarine induces inhibitory effects and downregulates CIP2A in lung cancer cells. ACS Med Chem Lett. 5:113–118. 2013. View Article : Google Scholar
13	Kosina P, Gregorova J, Gruz J, Vacek J, Kolar M, Vogel M, Roos W, Naumann K, Simanek V and Ulrichova J: Phytochemical and antimicrobial characterization of Macleaya cordata herb. Fitoterapia. 81:1006–1012. 2010. View Article : Google Scholar : PubMed/NCBI
14	Ouyang L, Su X, He D, Chen Y, Ma M, Xie Q and Yao S: A study on separation and extraction of four main alkaloids in Macleaya cordata (Willd) R. Br. with strip dispersion hybrid liquid membrane. J Sep Sci. 33:2026–2034. 2010. View Article : Google Scholar : PubMed/NCBI
15	Yao JY, Shen JY, Li XL, Xu Y, Hao GJ, Pan XY, Wang GX and Yin WL: Effect of sanguinarine from the leaves of Macleaya cordata against Ichthyophthirius multifiliis in grass carp (Ctenopharyngodon idella). Parasitol Res. 107:1035–1042. 2010. View Article : Google Scholar : PubMed/NCBI
16	Konda Y, Urano M, Harigaya Y and Onda M: Studies on the constituents of bocconia-cordata 0.4. Transformation of sanguinarine into bocconine. J Heterocycl Chem. 28:1841–1843. 1991. View Article : Google Scholar
17	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
18	Cao W, Liu Y, Zhang R, Zhang B, Wang T, Zhu X, Mei L, Chen H, Zhang H, Ming P, et al: Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci Rep. 5:84772015. View Article : Google Scholar : PubMed/NCBI
19	Liu X, Duan C, Ji J, Zhang T, Yuan X, Zhang Y, Ma W, Yang J, Yang L, Jiang Z, et al: Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells. Oncol Rep. 38:271–278. 2017. View Article : Google Scholar : PubMed/NCBI
20	Feng T, Cao W, Shen W, Zhang L, Gu X, Guo Y, Tsai HI, Liu X, Li J, Zhang J, et al: Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy. Oncotarget. 8:329–344. 2017.
21	Chou CC, Yang JS, Lu HF, Ip SW, Lo C, Wu CC, Lin JP, Tang NY, Chung JG, Chou MJ, et al: Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharm Res. 33:1181–1191. 2010. View Article : Google Scholar : PubMed/NCBI
22	Liu Y, Dong Y, Zhang B and Cheng YX: Small compound 6-O-angeloylplenolin induces caspase-dependent apoptosis in human multiple myeloma cells. Oncol Lett. 6:556–558. 2013. View Article : Google Scholar : PubMed/NCBI
23	Liu H, Gu Y, Wang H, Yin J, Zheng G, Zhang Z, Lu M, Wang C and He Z: Overexpression of PP2A inhibitor SET oncoprotein is associated with tumor progression and poor prognosis in human non-small cell lung cancer. Oncotarget. 6:14913–14925. 2015.PubMed/NCBI
24	Rincón R, Cristóbal I, Zazo S, Arpí O, Menéndez S, Manso R, Lluch A, Eroles P, Rovira A, Albanell J, et al: PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects. Oncotarget. 6:4299–4314. 2015. View Article : Google Scholar : PubMed/NCBI
25	Cristóbal I, Zazo S, Torrejón B, Pedregal M, Madoz-Gúrpide J, Lluch A, Eroles P, Rovira A, Albanell J, García-Foncillas J, et al: CIP2A confirms its prognostic value in triple-negative breast cancer. Oncogene. 36:3357–3358. 2017. View Article : Google Scholar : PubMed/NCBI
26	Balliu M, Cellai C, Lulli M, Laurenzana A, Torre E, Vannucchi AM and Paoletti F: HDAC1 controls CIP2A transcription in human colorectal cancer cells. Oncotarget. 7:25862–25871. 2016. View Article : Google Scholar : PubMed/NCBI
27	Huang Q, Qin S, Yuan X, Zhang L, Ji J, Liu X, Ma W, Zhang Y, Liu P, Sun Z, et al: Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A. Oncol Rep. 38:598–606. 2017. View Article : Google Scholar : PubMed/NCBI
28	Nicholson DW: Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6:1028–1042. 1999. View Article : Google Scholar : PubMed/NCBI
29	Johnstone RW, Ruefli AA and Lowe SW: Apoptosis: A link between cancer genetics and chemotherapy. Cell. 108:153–164. 2002. View Article : Google Scholar : PubMed/NCBI