Blocking COX-2 induces apoptosis and inhibits cell proliferation via the Akt/survivin- and Akt/ID3 pathway in low-grade-glioma
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Abstract
Approximately half of surgically-treated patients with low-grade-glioma (LGG) suffer recurrence or metastasis. Currently there is no effective drug treatment. While the selective COX-2 inhibitor celecoxib showed anti-neoplastic activity against several malignant tumors, its effects against LGG remain to be elucidated. Ours is the first report that the expression level of COX-2 in brain tissue samples from patients with LGG and in LGG cell lines is higher than in the non-neoplastic region and in normal brain cells. We found that celecoxib attenuated LGG cell proliferation in a dose-dependent manner. It inhibited the generation of prostaglandin E2 and induced apoptosis and cell-cycle arrest. We also show that celecoxib hampered the activation of the Akt/survivin- and the Akt/ID3 pathway in LGGs. These findings suggest that celecoxib may have a promising therapeutic potential and that the early treatment of LGG patients with the drug may be beneficial.
Keywords
COX-2 Low-grade glioma Akt Survivin ID3Notes
Acknowledgement
We thank Emiko Nishikawa for her excellent technical support.
Funding
This work was supported by a Grant-in-Aid for Scientific Research (JSPS KAKENHI Grant Number JP25462264), a Grant-in-Aid for Young Scientists (B) (JSPS KAKENHI Grant Number JP26861153).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary material
References
- 1.Forst DA, Nahed BV, Loeffler JS, Batchelor TT (2014) Low-grade gliomas. Oncologist 19:403–413CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Ding B, Gao M, Li Z, Xu C, Fan S, He W (2015) Expression of TYMS in lymph node metastasis from low-grade glioma. Oncol Lett 10:1569–1574PubMedPubMedCentralGoogle Scholar
- 3.Sareddy GR, Kesanakurti D, Kirti PB, Babu PP (2013) Nonsteroidal anti-inflammatory drugs diclofenac and celecoxib attenuate Wnt/b-catenin/Tcf signaling pathway in human glioblastoma cells. Neurochem Res 38:2313–2322CrossRefPubMedGoogle Scholar
- 4.Sareddy GR, Geeviman K, Ramulu C, Babu PP (2012) The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-kB pathway. J Neurooncol 106:99–109CrossRefPubMedGoogle Scholar
- 5.Qiu Y, Li X, Yi B et al (2015) Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting survivin phosphorylation and nuclear export in gallbladder cancer. Oncotarget 6:19148–19162CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Bai XM, Jiang H, Ding JX et al (2010) Prostaglandin E2 upregulates survivin expression via the EP1 receptor in hepatocellular carcinoma cells. Life Sci 86:214–223CrossRefPubMedGoogle Scholar
- 7.Xu K, Wang L, Shu HK (2014) COX-2 overexpression increases malignant potential of human glioma cells through Id1. Oncotarget 5:1241–1252CrossRefPubMedGoogle Scholar
- 8.Vandeputte DA, Troost D, Leenstra S et al (2002) Expression and distribution of Id helix-loop-helix proteins in human astrocytic tumors. Glia 38:329–338CrossRefPubMedGoogle Scholar
- 9.Sampetrean O, Saga I, Nakanishi M, Sugihara E, Fukaya R, Onishi N, Osuka S, Akahata M, Kai K, Sugimoto H, Hirao A, Saya H (2011) Invasion precedes tumor mass formation in a malignant brain tumor model of genetically modified neural stem cells. Neoplasia 13:784–791CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Saga I, Shibao S, Okubo J, Osuka S, Kobayashi Y, Yamada S, Fujita S, Urakami K, Kusuhara M, Yoshida K, Saya H, Sampetrean O (2014) Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model. Neurooncol 16:1048–1056Google Scholar
- 11.Lee HC, Park IC, Park MJ et al. (2005) Sulindac and its metabolites inhibit invasion of glioblastoma cells via down-regulation of Akt/PKB and MMP-2. J Cell Biochem 94:597–610CrossRefPubMedGoogle Scholar
- 12.Siegelin MD, Reuss DE, Habel A, Rami A, von Deimling A (2009) Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells. Neurooncol 11:122–131Google Scholar
- 13.Jin X, Yin J, Kim SH et al (2011) EGFR-Akt-smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res 71:7125–7134CrossRefPubMedGoogle Scholar
- 14.Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, Black PM (2000) Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res 60:4926–4931PubMedGoogle Scholar
- 15.Panel V, Boëlle PY, Ayala-Sanmartin J et al (2006) Cytoplasmic phospholipase A2 expression in human colon adenocarcinoma is correlated with cyclooxygenase-2 expression and contributes to prostaglandin E2 production. Cancer Lett 243:255–263CrossRefPubMedGoogle Scholar
- 16.Kern MA, Haugg AM, Koch AF et al (2006) Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. Cancer Res 66:7059–7066CrossRefPubMedGoogle Scholar
- 17.Kurtova AV, Xiao J, Mo Q et al (2015) Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517:209–213CrossRefPubMedGoogle Scholar
- 18.Arico S, Pattingre S, Bauvy C et al (2002) Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem 277:27613–27621CrossRefPubMedGoogle Scholar
- 19.Xie SQ, Zhang YH, Li Q et al (2012) COX-2-independent induction of apoptosis by celecoxib and polyamine naphthalimide conjugate mediated by polyamine depression in colorectal cancer cell lines. Int J Colorectal Dis 27:861–868CrossRefPubMedGoogle Scholar
- 20.Mure H, Matsuzaki K, Kitazato KT et al. (2010) Akt2 and Akt3 play a pivotal role in malignant gliomas. Neurooncol 12:221–232Google Scholar
- 21.Chautard E, Ouédraogo ZG, Biau J, Verrelle P (2014) Role of Akt in human malignant glioma: from oncogenesis to tumor aggressiveness. J Neurooncol 117:205–215CrossRefPubMedGoogle Scholar
- 22.Dandekar DS, Lopez M, Carey RI, Lokeshwar BL (2005) Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells. Int J Cancer 115:484–492CrossRefPubMedGoogle Scholar
- 23.Angileri FF, Aguennouz M, Conti A et al (2008) Nuclear factor-kappa B activation and differential expression of survivin and Bcl-2 in human grade 2–4 astrocytomas. Cancer 112:2258–2266CrossRefPubMedGoogle Scholar
- 24.Phi JH, Choi SA, Lim SH et al (2013) ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma. BMC Cancer 13:1–16CrossRefGoogle Scholar
- 25.Jin X, Jin X, Sohn YW et al (2013) Blockade of EGFR signaling promotes glioma stem-like cell invasiveness by abolishing ID3-mediated inhibition of p27KIP1 and MMP3 expression. Cancer Lett 328:235–242CrossRefPubMedGoogle Scholar
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