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Article

Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a

  • Authors:
    • Ling Jiang
    • Xiao-Cheng Cao
    • Jian-Guo Cao
    • Fei Liu
    • Mei-Fang Quan
    • Xi-Feng Sheng
    • Kai-Qun Ren
  • View Affiliations / Copyright

    Affiliations: Department of Gynaecology and Obstetrics, The People's Hospital of Hunan Province, First Affiliated Hospital of Hunan Normal University, Changsha 410005, P.R. China, Laboratory of Medicine Engineering, Medical College, Hunan Normal University, Changsha 410013, P.R. China
  • Pages: 1605-1610
    |
    Published online on: March 14, 2013
       https://doi.org/10.3892/ol.2013.1258
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Abstract

Casticin, a polymethoxyflavone, is reported to have anticancer activities. The aim of the present study was to examine the molecular mechanisms by which casticin induces apoptosis in ovarian cancer cells. The human ovarian cancer cell lines SKOV3 and A2780 were cultured in vitro. Various molecular techniques, including histone/DNA enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR), western blot analysis and gene transfection, were used to assess the expression of FOXO3a and forkhead box protein M1 (FoxM1) in casticin-treated ovarian cancer cell lines. Casticin-induced apoptotic cell death was accompanied by the activation of transcription factor FOXO3a, with a concomitant decrease in the expression levels of FoxM1 and its downstream target factors, namely survivin and polo‑like kinase 1 (PLK1), and an increase in p27KIP1. A small inhibitory RNA (siRNA) knockout of FoxM1 potentiated casticin-induced apoptosis in ovarian cancer cells. Silencing FOXO3a expression using siRNA increased FoxM1 expression levels and clearly attenuated the induction of apoptosis by casticin treatment. These results show that casticin-induced apoptosis in ovarian cancer may be caused by the activation of FOXO3a, leading to FoxM1 inhibition.
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1 

Lan C, Chenggang W, Yulan B, Xiaohui D, Junhui Z and Xiao W: Aberrant expression of WWOX protein in epithelial ovarian cancer: a clinicopathologic and immunohistochemical study. Int J Gynecol Pathol. 31:125–132. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Vlahovic G, Meadows KL, Uronis HE, et al: A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors. Cancer Chemother Pharmacol. 70:95–102. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Hennessy BT, Coleman RL and Markman M: Ovarian cancer. Lancet. 374:1371–1382. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Lin S, Zhang H, Han T, Wu JZ, Rahman K and Qin LP: In vivo effect of casticin on acute inflammation. Zhong Xi Yi Jie He Xue Bao. 5:573–576. 2007. View Article : Google Scholar

5 

Li WX, Cui CB, Cai B, Wang HY and Yao XS: Flavonoids from Vitex trifolia Linhibit cell cycle progression at G2/M phase and induce apoptosis in mammalian cancer cells. J Asian Nat Prod Res. 7:615–626. 2005.

6 

Chen D, Cao J, Tian L, Liu F and Sheng X: Induction of apoptosis by casticin in cervical cancer cells through reactive oxygen species-mediated mitochondrial signaling pathways. Oncol Rep. 26:1287–1294. 2011.PubMed/NCBI

7 

Zeng F, Tian L, Liu F, Cao J, Quan M and Sheng X: Induction of apoptosis by casticin in cervical cancer cells: reactive oxygen species-dependent sustained activation of Jun N-terminal kinase. Acta Biochim Biophys Sin (Shanghai). 44:442–449. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Díaz F, Chávez D, Lee D, et al: Cytotoxic flavone analogues of vitexicarpin, a constituent of the leaves of Vitex negundo. J Nat Prod. 66:865–867. 2003.PubMed/NCBI

9 

Haïdara K, Zamir L, Shi QW and Batist G: The flavonoid Casticin has multiple mechanisms of tumor cytotoxicity action. Cancer Lett. 242:180–190. 2006.PubMed/NCBI

10 

Imai M, Kikuchi H, Denda T, Ohyama K, Hirobe C and Toyoda H: Cytotoxic effects of flavonoids against a human colon cancer derived cell line, COLO 201: a potential natural anti-cancer substance. Cancer Lett. 276:74–80. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Yang J, Yang Y, Tian L, Sheng XF, Liu F and Cao JG: Casticin-induced apoptosis involves death receptor 5 upregulation in hepatocellular carcinoma cells. World J Gastroenterol. 17:4298–4307. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Hernández MM, Heraso C, Villarreal ML, Vargas-Arispuro I and Aranda E: Biological activities of crude plant extracts from Vitex trifolia L. (Verbenaceae). J Ethnopharmacol. 67:37–44. 1999.

13 

Hannenhalli S and Kaestner KH: The evolution of Fox genes and their role in development and disease. Nat Rev Genet. 10:233–240. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Korver W, Roose J and Clevers H: The winged-helix transcription factor Trident is expressed in cycling cells. Nucleic Acids Res. 25:1715–1719. 1997. View Article : Google Scholar : PubMed/NCBI

15 

Kwok JM, Peck B, Monteiro LJ, et al: FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol Cancer Res. 8:24–34. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Bergamaschi A, Christensen BL and Katzenellenbogen BS: Reversal of endocrine resistance in breast cancer: interrelationships among 14-3-3ζ, FOXM1, and a gene signature associated with mitosis. Breast Cancer Res. 13:R702011.PubMed/NCBI

17 

Feo F, Frau M and Pascale RM: Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. World J Gastroenterol. 14:6601–6615. 2008. View Article : Google Scholar

18 

Chen W, Yuan K, Tao ZZ and Xiao BK: Deletion of Forkhead Box M1 transcription factor reduces malignancy in laryngeal squamous carcinoma cells. Asian Pac J Cancer Prev. 12:1785–1788. 2011.PubMed/NCBI

19 

Halasi M and Gartel AL: Suppression of FOXM1 sensitizes human cancer cells to cell death induced by DNA-damage. PLoS One. 7:e317612012. View Article : Google Scholar : PubMed/NCBI

20 

Wonsey DR and Follettie MT: Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res. 65:5181–5189. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Down CF, Millour J, Lam EW and Watson RJ: Binding of FoxM1 to G2/M gene promoters is dependent upon B-Myb. Biochim Biophys Acta. 1819:855–862. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Millour J, de Olano N, Horimoto Y, et al: ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther. 10:1046–1058. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Schüller U, Zhao Q, Godinho SA, et al: Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors. Mol Cell Biol. 27:8259–8270. 2007.PubMed/NCBI

24 

Fu Z, Malureanu L, Huang J, et al: PLK1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat Cell Biol. 10:1076–1082. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Laoukili J, Alvarez-Fernandez M, Stahl M and Medema RH: FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner. Cell Cycle. 7:2720–2726. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Delpuech O, Griffiths B, East P, et al: Induction of Mxi1-SR alpha by FOXO3a contributes to repression of Myc-dependent gene expression. Mol Cell Biol. 27:4917–4930. 2007. View Article : Google Scholar : PubMed/NCBI

27 

McGovern UB, Francis RE, Peck B, et al: Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol Cancer Ther. 8:582–591. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Wilson MS, Brosens JJ, Schwenen HD and Lam EW: FOXO and FOXM1 in cancer: the FOXO-FOXM1 axis shapes the outcome of cancer chemotherapy. Curr Drug Targets. 12:1256–1266. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Fang L, Wang H, Zhou L and Yu D: Akt-FOXO3a signaling axis dysregulation in human oral squamous cell carcinoma and potent efficacy of FOXO3a-targeted gene therapy. Oral Oncol. 47:16–21. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Lam M, Carmichael AR and Griffiths HR: An aqueous extract of Fagonia cretica induces DNA damage, cell cycle arrest and apoptosis in breast cancer cells via FOXO3a and p53 expression. PLoS One. 7:e401522012.PubMed/NCBI

31 

Yusuf I, Zhu X, Kharas MG, Chen J and Fruman DA: Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors. Blood. 104:784–787. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Wang Z, Ahmad A, Banerjee S, et al: FoxM1 is a novel target of a natural agent in pancreatic cancer. Pharm Res. 27:1159–1168. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Ning Y, Li Q, Xiang H, Liu F and Cao J: Apoptosis induced by 7-difluoromethoxyl-5,4’-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells. Oncol Rep. 27:1857–1864. 2012.PubMed/NCBI

34 

Bellelli R, Castellone MD, Garcia-Rostan G, et al: FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma. Endocr Relat Cancer. 19:695–710. 2012. View Article : Google Scholar : PubMed/NCBI

35 

Dibb M, Han N, Choudhury J, et al: The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma. Br J Cancer. 107:1766–1775. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Ha SY, Lee CH, Chang HK, et al: Differential expression of forkhead box M1 and its downstream cyclin-dependent kinase inhibitors p27(kip1) and p21(waf1/cip1) in the diagnosis of pulmonary neuroendocrine tumours. Histopathology. 60:731–739. 2012. View Article : Google Scholar

37 

Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar

38 

Petrovic V, Costa RH, Lau LF, Raychaudhuri P and Tyner AL: FoxM1 regulates growth factor-induced expression of kinase-interacting stathmin (KIS) to promote cell cycle progression. J Biol Chem. 283:453–460. 2008. View Article : Google Scholar : PubMed/NCBI

39 

Kwok JM, Myatt SS, Marson CM, Coombes RC, Constantinidou D and Lam EW: Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol Cancer Ther. 7:2022–2032. 2008. View Article : Google Scholar : PubMed/NCBI

40 

Petrovic V, Costa RH, Lau LF, Raychaudhuri P and Tyner AL: Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin. Cancer Biol Ther. 9:1008–1016. 2010. View Article : Google Scholar : PubMed/NCBI

41 

Roy SK, Srivastava RK and Shankar S: Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal. 5:102010. View Article : Google Scholar : PubMed/NCBI

42 

Zanella F, Link W and Carnero A: Understanding FOXO, new views on old transcription factors. Curr Cancer Drug Targets. 10:135–146. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Myatt SS and Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Jiang L, Cao X, Cao J, Liu F, Quan M, Sheng X and Ren K: Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a. Oncol Lett 5: 1605-1610, 2013.
APA
Jiang, L., Cao, X., Cao, J., Liu, F., Quan, M., Sheng, X., & Ren, K. (2013). Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a. Oncology Letters, 5, 1605-1610. https://doi.org/10.3892/ol.2013.1258
MLA
Jiang, L., Cao, X., Cao, J., Liu, F., Quan, M., Sheng, X., Ren, K."Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a". Oncology Letters 5.5 (2013): 1605-1610.
Chicago
Jiang, L., Cao, X., Cao, J., Liu, F., Quan, M., Sheng, X., Ren, K."Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a". Oncology Letters 5, no. 5 (2013): 1605-1610. https://doi.org/10.3892/ol.2013.1258
Copy and paste a formatted citation
x
Spandidos Publications style
Jiang L, Cao X, Cao J, Liu F, Quan M, Sheng X and Ren K: Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a. Oncol Lett 5: 1605-1610, 2013.
APA
Jiang, L., Cao, X., Cao, J., Liu, F., Quan, M., Sheng, X., & Ren, K. (2013). Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a. Oncology Letters, 5, 1605-1610. https://doi.org/10.3892/ol.2013.1258
MLA
Jiang, L., Cao, X., Cao, J., Liu, F., Quan, M., Sheng, X., Ren, K."Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a". Oncology Letters 5.5 (2013): 1605-1610.
Chicago
Jiang, L., Cao, X., Cao, J., Liu, F., Quan, M., Sheng, X., Ren, K."Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a". Oncology Letters 5, no. 5 (2013): 1605-1610. https://doi.org/10.3892/ol.2013.1258
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