Corosolic acid induces cell cycle arrest and cell apoptosis in human retinoblastoma Y-79 cells via disruption of MELK-FoxM1 signaling

Wang,Ke; Zhu,Xue; Yao,Yong; Yang,Min; Zhou,Fanfan; Zhu,Ling

doi:10.3892/or.2018.6339

Corosolic acid induces cell cycle arrest and cell apoptosis in human retinoblastoma Y-79 cells via disruption of MELK-FoxM1 signaling

Authors:
- Ke Wang
- Xue Zhu
- Yong Yao
- Min Yang
- Fanfan Zhou
- Ling Zhu
View Affiliations

Affiliations: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, P.R. China, Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, P.R. China, Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2000, Australia, Save Sight Institute, University of Sydney, Sydney, NSW 2000, Australia
Published online on: March 28, 2018 https://doi.org/10.3892/or.2018.6339
Pages: 2777-2786

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

Retinoblastoma (Rb) is the most frequent primary intraocular tumor usually diagnosed in infants and children, and current therapy for such disease is still limited. Corosolic acid (CA), an ursane-type pentacyclic triterpene, has been assessed as a promising anticancer agent with little impact on untransformed cells. In the present study, we investigated the cytotoxic effect and underlying mechanism of CA on human retinoblastoma Y-79 cells. The viability of cells was verified by MTT assay. Cell cycle and apoptosis were evaluated by flow cytometric analysis. The expressions and activities of the related molecules were assessed by western blot analysis and luciferase assay. The results demonstrated that the treatment of CA dose-dependently induced cytotoxicity, cell cycle arrest and cell apoptosis in Y-79 cells. Furthermore, MELK-FoxM1 signaling was estimated to be involved in the cytotoxic effect of CA on Y-79 cells, and CA exerted its activity mainly through inhibition of the expression levels of MELK and FoxM1 as well as through suppression of the transcriptional activity of FoxM1 driven by itself or MELK. Our findings establish MELK-FoxM1 signaling as a promising therapeutic target for human retinoblastoma, and suggest the potential development of CA and its derivatives as novel drug candidates against this disease.

View Figures

View References

1	Kivelä T: The epidemiological challenge of the most frequent eye cancer: Retinoblastoma, an issue of birth and death. Br J Ophthalmol. 93:1129–1131. 2009. View Article : Google Scholar : PubMed/NCBI
2	Park SJ, Woo SJ and Park KH: Incidence of retinoblastoma and survival rate of retinoblastoma patients in Korea using the Korean National Cancer Registry database (1993–2010). Invest Ophthalmol Vis Sci. 55:2816–2821. 2014. View Article : Google Scholar : PubMed/NCBI
3	Waddell KM, Kagame K, Ndamira A, Twinamasiko A, Picton SV, Simmons IG, Johnston WT and Newton R: Clinical features and survival among children with retinoblastoma in Uganda. Br J Ophthalmol. 99:387–390. 2015. View Article : Google Scholar : PubMed/NCBI
4	McEvoy JD and Dyer MA: Genetic and epigenetic discoveries in human retinoblastoma. Crit Rev Oncog. 20:217–225. 2015. View Article : Google Scholar : PubMed/NCBI
5	DiCiommo D, Gallie BL and Bremner R: Retinoblastoma: The disease, gene and protein provide critical leads to understand cancer. Semin Cancer Biol. 10:255–269. 2000. View Article : Google Scholar : PubMed/NCBI
6	Meel R, Radhakrishnan V and Bakhshi S: Current therapy and recent advances in the management of retinoblastoma. Indian J Med Paediatr Oncol. 33:80–88. 2012. View Article : Google Scholar : PubMed/NCBI
7	Kim JY and Park Y: Treatment of Retinoblastoma: The role of external beam radiotherapy. Yonsei Med J. 56:1478–1491. 2015. View Article : Google Scholar : PubMed/NCBI
8	Ye J, Lou L, Jin K, Xu Y, Ye X, Moss T and McBain H: Vision-related quality of life and appearance concerns are associated with anxiety and depression after eye enucleation: A cross-sectional study. PLoS One. 10:e01364602015. View Article : Google Scholar : PubMed/NCBI
9	Marees T, Moll AC, Imhof SM, de Boer MR, Ringens PJ and van Leeuwen FE: Risk of second malignancies in survivors of retinoblastoma: More than 40 years of follow-up. J Natl Cancer Inst. 100:1771–1779. 2008. View Article : Google Scholar : PubMed/NCBI
10	Temming P, Arendt M, Viehmann A, Eisele L, Le Guin CH, Schündeln MM, Biewald E, Astrahantseff K, Wieland R, Bornfeld N, et al: Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center. Pediatr Blood Cancer. 64:71–80. 2017. View Article : Google Scholar : PubMed/NCBI
11	Mazumder K, Tanaka K and Fukase K: Cytotoxic activity of ursolic acid derivatives obtained by isolation and oxidative derivatization. Molecules. 18:8929–8944. 2013. View Article : Google Scholar : PubMed/NCBI
12	Shan JZ, Xuan YY, Zheng S, Dong Q and Zhang SZ: Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J Zhejiang Univ Sci B. 10:668–674. 2009. View Article : Google Scholar : PubMed/NCBI
13	Leng S, Hao Y, Du D, Xie S, Hong L, Gu H, Zhu X, Zhang J, Fan D and Kung HF: Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. Int J Cancer. 133:2781–2790. 2013.PubMed/NCBI
14	Kim SH, Ryu HG, Lee J, Shin J, Harikishore A, Jung HY, Kim YS, Lyu HN, Oh E, Baek NI, et al: Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells. Sci Rep. 5:145702015. View Article : Google Scholar : PubMed/NCBI
15	Weng H, Tan ZJ, Hu YP, Shu YJ, Bao RF, Jiang L, Wu XS, Li ML, Ding Q, Wang XA, et al: Ursolic acid induces cell cycle arrest and apoptosis of gallbladder carcinoma cells. Cancer Cell Int. 14:962014. View Article : Google Scholar : PubMed/NCBI
16	Huang CY, Lin CY, Tsai CW and Yin MC: Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. Toxicol In Vitro. 25:1274–1280. 2011. View Article : Google Scholar : PubMed/NCBI
17	Sung B, Kang YJ, Kim DH, Hwang SY, Lee Y, Kim M, Yoon JH, Kim CM, Chung HY and Kim ND: Corosolic acid induces apoptotic cell death in HCT116 human colon cancer cells through a caspase-dependent pathway. Int J Mol Med. 33:943–949. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zona S, Bella L, Burton MJ, de Moraes Nestal G and Lam EW: FOXM1: An emerging master regulator of DNA damage response and genotoxic agent resistance. Biochim Biophys Acta. 1839:1316–1322. 2014. View Article : Google Scholar : PubMed/NCBI
19	Koo CY, Muir KW and Lam EW: FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta. 1819:28–37. 2012. View Article : Google Scholar : PubMed/NCBI
20	Ganguly R, Mohyeldin A, Thiel J, Kornblum HI, Beullens M and Nakano I: MELK - a conserved kinase: Functions, signaling, cancer, and controversy. Clin Transl Med. 4:112015. View Article : Google Scholar : PubMed/NCBI
21	Joshi K, Banasavadi-Siddegowda Y, Mo X, Kim SH, Mao P, Kig C, Nardini D, Sobol RW, Chow LM, Kornblum HI, et al: MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells. 31:1051–1063. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wang JS, Ren TN and Xi T: Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-7 human breast cancer cells. Med Oncol. 29:10–15. 2012. View Article : Google Scholar : PubMed/NCBI
23	van Meerloo J, Kaspers GJ and Cloos J: Cell sensitivity assays: The MTT assay. Methods Mol Biol. 731:237–245. 2011. View Article : Google Scholar : PubMed/NCBI
24	Zhu X, Wang K, Zhang K, Zhang T, Yin Y and Xu F: Ziyuglycoside I inhibits the proliferation of MDA-MB-231 breast carcinoma cells through Inducing p53-mediated G2/M cell cycle arrest and intrinsic/extrinsic apoptosis. Int J Mol Sci. 17:19032016. View Article : Google Scholar
25	Wang K, Zhu X, Zhang K, Wu Z, Sun S, Zhou F and Zhu L: Neuroprotective effect of puerarin on glutamate-induced cytotoxicity in differentiated Y-79 cells via inhibition of ROS generation and Ca²⁺ influx. Int J Mol Sci. 17:E11092016. View Article : Google Scholar : PubMed/NCBI
26	Smale ST: Luciferase assay. Cold Spring Harb Protoc 2010: pdb prot5421. doi: 10.1101/pdb.prot5421.
27	Wang Y, Lee YM, Baitsch L, Huang A, Xiang Y, Tong H, Lako A, Von T, Choi C, Lim E, et al: MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. eLife. 3:e017632014. View Article : Google Scholar : PubMed/NCBI
28	Lin ML, Park JH, Nishidate T, Nakamura Y and Katagiri T: Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res. 9:R172007. View Article : Google Scholar : PubMed/NCBI
29	Jiang L, Wang P, Chen L and Chen H: Down-regulation of FoxM1 by thiostrepton or small interfering RNA inhibits proliferation, transformation ability and angiogenesis, and induces apoptosis of nasopharyngeal carcinoma cells. Int J Clin Exp Pathol. 7:5450–5460. 2014.PubMed/NCBI
30	Ku CY, Wang YR, Lin HY, Lu SC and Lin JY: Corosolic acid inhibits hepatocellular carcinoma cell migration by targeting the VEGFR2/Src/FAK pathway. PLoS One. 10:e01267252015. View Article : Google Scholar : PubMed/NCBI
31	Yoo KH, Park JH, Lee DY, Hwang-Bo J, Baek NI and Chung IS: Corosolic acid exhibits anti-angiogenic and anti-lymphangiogenic effects on in vitro endothelial cells and on an in vivo CT-26 colon carcinoma animal model. Phytother Res. 29:714–723. 2015. View Article : Google Scholar : PubMed/NCBI
32	Lee HS, Park JB, Lee MS, Cha EY, Kim JY and Sul JY: Corosolic acid enhances 5-fluorouracil-induced apoptosis against SNU-620 human gastric carcinoma cells by inhibition of mammalian target of rapamycin. Mol Med Rep. 12:4782–4788. 2015. View Article : Google Scholar : PubMed/NCBI
33	Wierstra I: The transcription factor FOXM1 (Forkhead box M1): Proliferation-specific expression, transcription factor function, target genes, mouse models, and normal biological roles. Adv Cancer Res. 118:97–398. 2013. View Article : Google Scholar : PubMed/NCBI
34	Laoukili J, Kooistra MR, Brás A, Kauw J, Kerkhoven RM, Morrison A, Clevers H and Medema RH: FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol. 7:126–136. 2005. View Article : Google Scholar : PubMed/NCBI
35	Wierstra I: FOXM1 (Forkhead box M1) in tumorigenesis: Overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties, and target of anticancer therapy. Adv Cancer Res. 119:191–419. 2013. View Article : Google Scholar : PubMed/NCBI
36	Aytes A, Mitrofanova A, Lefebvre C, Alvarez MJ, Castillo-Martin M, Zheng T, Eastham JA, Gopalan A, Pienta KJ, Shen MM, et al: Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell. 25:638–651. 2014. View Article : Google Scholar : PubMed/NCBI
37	de Moraes Nestal G, Delbue D, Silva KL, Robaina MC, Khongkow P, Gomes AR, Zona S, Crocamo S, Mencalha AL, Magalhães LM, et al: FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance. Cell Signal. 27:2496–2505. 2015. View Article : Google Scholar : PubMed/NCBI
38	Ganguly R, Hong CS, Smith LG, Kornblum HI and Nakano I: Maternal embryonic leucine zipper kinase: Key kinase for stem cell phenotype in glioma and other cancers. Mol Cancer Ther. 13:1393–1398. 2014. View Article : Google Scholar : PubMed/NCBI
39	Xia H, Kong SN, Chen J, Shi M, Sekar K, Seshachalam VP, Rajasekaran M, Goh BKP, Ooi LL and Hui KM: MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence. Cancer Lett. 383:85–93. 2016. View Article : Google Scholar : PubMed/NCBI