Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells

Cheng,Chao; Jiao,Jian‑Tong; Qian,Yu; Guo,Xiao‑Yi; Huang,Jin; Dai,Min‑Chao; Zhang,Lei; Ding,Xiao‑Peng; Zong,Da; Shao,Jun‑Fei

doi:10.3892/mmr.2016.5037

Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells

Authors:
- Chao Cheng
- Jian‑Tong Jiao
- Yu Qian
- Xiao‑Yi Guo
- Jin Huang
- Min‑Chao Dai
- Lei Zhang
- Xiao‑Peng Ding
- Da Zong
- Jun‑Fei Shao
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Affiliations: Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
Published online on: March 21, 2016 https://doi.org/10.3892/mmr.2016.5037
Pages: 3763-3770
Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has previously been demonstrated that curcumin possesses an antitumor activity, which is associated with its ability to induce G2/M cell cycle arrest and apoptosis. However the detailed underlying mechanisms remain unclear. The present study aimed to investigate the efficacy and underlying mechanism of curcumin‑induced cell cycle arrest and apoptosis in U87 human glioblastoma cells. By immunofluorescence staining, subcellular fractionation and western blotting, the present study demonstrated that curcumin was able to induce G2/M cell cycle arrest and apoptosis by increasing the expression levels of cyclin G2, cleaved caspase‑3 and Fas ligand (FasL), and decreasing the expression of cyclin‑dependent kinase 1 (CDK1). In addition, increased expression of forkhead box protein O1 (FoxO1) and decreased expression of phosphorylated (p)‑FoxO1 were detected in the curcumin‑treated U87 cells. Curcumin was also able to induce the translocation of FoxO1 from the cytoplasm to the nucleus. Furthermore, following knockdown of FoxO1 expression in curcumin‑treated U87 cells using FoxO1 small interfering RNA, the expression levels of cyclin G2, cleaved caspase‑3 and FasL were inhibited; however, the expression levels of CDK1 were not markedly altered. Notably, following knockdown of CDK1 expression under normal conditions, the total expression of FoxO1 was not affected; however, p‑FoxO1 expression was decreased and FoxO1 nuclear expression was increased. Furthermore, curcumin‑induced G2/M cell cycle arrest and apoptosis could be attenuated by FoxO1 knockdown. These results indicated that curcumin may induce G2/M cell cycle arrest and apoptosis in U87 cells by increasing FoxO1 expression. The present study identified a novel mechanism underlying the antitumor effects of curcumin, and may provide a theoretical basis for the application of curcumin in glioma treatment.

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1	Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M and Fisher J; NABTT CNS Consortium: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res. 16:2443–2449. 2010. View Article : Google Scholar : PubMed/NCBI
2	Garodia P, Ichikawa H, Malani N, Sethi G and Aggarwal BB: From ancient medicine to modern medicine: Ayurvedic concepts of health and their role in inflammation and cancer. J Soc Integr Oncol. 5:25–37. 2007. View Article : Google Scholar : PubMed/NCBI
3	Cole GM, Teter B and Frautschy SA: Neuroprotective effects of curcumin. Adv Exp Med Biol. 595:197–212. 2007. View Article : Google Scholar : PubMed/NCBI
4	Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, Hsieh CY and Cheng AL: Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis. 21:331–335. 2000. View Article : Google Scholar : PubMed/NCBI
5	Lim GP, Chu T, Yang F, Beech W, Frautschy SA and Cole GM: The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 21:8370–8377. 2001.PubMed/NCBI
6	Thiyagarajan M and Sharma SS: Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci. 74:969–985. 2004. View Article : Google Scholar
7	LoTempio MM, Veena MS, Steele HL, Ramamurthy B, Ramalingam TS, Cohen AN, Chakrabarti R, Srivatsan ES and Wang MB: Curcumin suppresses growth of head and neck squamous cell carcinoma. Clin Cancer Res. 11:6994–7002. 2005. View Article : Google Scholar : PubMed/NCBI
8	Wang D, Veena MS, Stevenson K, Tang C, Ho B, Suh JD, Duarte VM, Faull KF, Mehta K, Srivatsan ES and Wang MB: Liposome-encapsulated curcumin suppresses growth of head and neck squamous cell carcinoma in vitro and in xenografts through the inhibition of nuclear factor kappaB by an AKT-independent pathway. Clin Cancer Res. 14:6228–6236. 2008. View Article : Google Scholar : PubMed/NCBI
9	Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN, Kamat AA, Spannuth WA, Gershenson DM, Lutgendorf SK, et al: Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res. 13:3423–3430. 2007. View Article : Google Scholar : PubMed/NCBI
10	Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q and Liang Z: Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci. 103:684–690. 2012. View Article : Google Scholar
11	Kumar A, Ahuja A, Ali J and Baboota S: Curcumin-loaded lipid nanocarrier for improving bioavailability, stability and cytotoxicity against malignant glioma cells. Drug Deliv. 23:214–229. 2016. View Article : Google Scholar
12	Greer EL and Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 24:7410–7425. 2005. View Article : Google Scholar : PubMed/NCBI
13	Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, et al: IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 117:225–237. 2004. View Article : Google Scholar : PubMed/NCBI
14	Taylor S, Lam M, Pararasa C, Brown JE, Carmichael AR and Griffiths HR: Evaluating the evidence for targeting FOXO3a in breast cancer: A systematic review. Cancer Cell Int. 15:12015. View Article : Google Scholar : PubMed/NCBI
15	Yang H, Zhao R, Yang HY and Lee MH: Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene. 24:1924–1935. 2005. View Article : Google Scholar : PubMed/NCBI
16	Ramaswamy S, Nakamura N, Sansal I, Bergeron L and Sellers WR: A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell. 2:81–91. 2002. View Article : Google Scholar : PubMed/NCBI
17	Prakobwong S, Gupta SC, Kim JH, Sung B, Pinlaor P, Hiraku Y, Wongkham S, Sripa B, Pinlaor S and Aggarwal BB: Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways. Carcinogenesis. 32:1372–1380. 2011. View Article : Google Scholar : PubMed/NCBI
18	Moragoda L, Jaszewski R and Majumdar AP: Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res. 21:873–878. 2001.PubMed/NCBI
19	Shao J, Zheng D, Jiang Z, Xu H, Hu Y, Li X and Lu X: Curcumin delivery by methoxy polyethylene glycol-poly (caprolactone) nanoparticles inhibits the growth of C6 glioma cells. Acta Biochim Biophys Sin (Shanghai). 43:267–274. 2011. View Article : Google Scholar
20	Vallianou NG, Evangelopoulos A, Schizas N and Kazazis C: Potential anticancer properties and mechanisms of action of curcumin. Anticancer Res. 35:645–651. 2015.PubMed/NCBI
21	Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridandapani S, Anant S and Kuppusamy P: Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther. 6:178–184. 2007. View Article : Google Scholar : PubMed/NCBI
22	Luthra PM, Kumar R and Prakash A: Demethoxycurcumin induces Bcl-2 mediated G2/M arrest and apoptosis in human glioma U87 cells. Biochem Biophys Res Commun. 384:420–425. 2009. View Article : Google Scholar : PubMed/NCBI
23	Guo H, Xu YM, Ye ZQ, Yu JH and Hu XY: Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor. Pharmazie. 68:431–434. 2013.PubMed/NCBI
24	Huang H and Tindall DJ: Dynamic FoxO transcription factors. J Cell Sci. 120:2479–2487. 2007. View Article : Google Scholar : PubMed/NCBI
25	Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI
26	Biggs WH III, Cavenee WK and Arden KC: Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse. Mamm Genome. 12:416–425. 2001. View Article : Google Scholar : PubMed/NCBI
27	Furuyama T, Nakazawa T, Nakano I and Mori N: Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J. 349:629–634. 2000. View Article : Google Scholar : PubMed/NCBI
28	Lin K, Dorman JB, Rodan A and Kenyon C: daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 278:1319–1322. 1997. View Article : Google Scholar : PubMed/NCBI
29	Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA and Ruvkun G: The fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 389:994–999. 1997. View Article : Google Scholar : PubMed/NCBI
30	Huang H, Regan KM, Lou Z, Chen J and Tindall DJ: CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 314:294–297. 2006. View Article : Google Scholar : PubMed/NCBI
31	Modur V, Nagarajan R, Evers BM and Milbrandt J: FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem. 277:47928–47937. 2002. View Article : Google Scholar : PubMed/NCBI
32	Dijkers PF, Medema RH, Lammers JW, Koenderman L and Coffer PJ: Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 10:1201–1204. 2000. View Article : Google Scholar : PubMed/NCBI
33	Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM and Medema RH: The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol. 168:5024–5031. 2002. View Article : Google Scholar : PubMed/NCBI