Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

Liu,Xiaoyang; Wang,Libo; Chen,Jiajun; Ling,Qi; Wang,Hongfei; Li,Shilin; Li,Liming; Yang,Shuping; Xia,Mingying; Jing,Ling

doi:10.3892/mmr.2014.2811

Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

Authors:
- Xiaoyang Liu
- Libo Wang
- Jiajun Chen
- Qi Ling
- Hongfei Wang
- Shilin Li
- Liming Li
- Shuping Yang
- Mingying Xia
- Ling Jing
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Affiliations: School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China, Jilin Medical College, Jilin, Jilin 132013, P.R. China, Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai 200433, P.R. China
Published online on: October 29, 2014 https://doi.org/10.3892/mmr.2014.2811
Pages: 1516-1522

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Abstract

Glioma is the most common primary brain tumor among adults. Temozolomide (TMZ) is widely used as the first‑line postsurgical drug for malignant glioma. However, the therapeutic efficacy of TMZ remains ineffective as inherited or acquired drug resistance is frequently observed. Estrogen receptor β (ERβ) has emerged as a tumor suppressor and a key regulator of signal transduction in glioma cells. However, little is known about the role of ERβ in regulating the chemotherapeutic response to TMZ. In the current study, the TMZ‑resistant U138 glioma cells were treated with the novel ERβ agonist liquiritigenin (Liq). It was observed that Liq significantly enhanced ERβ expression and sensitized glioma cells to TMZ‑induced proliferation inhibition. As a potential mechanism, it was noted that Liq treatment significantly inhibited the activity of the PI3K/AKT/mTOR pathway, which played a protective role against the TMZ‑induced cytotoxicity. In addition, it was demonstrated that ERβ knockdown or activation of the phosphatidylinositol‑4,5‑bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway by insulin‑like growth factor 1 both eradicated the function of Liq. These results suggest that Liq treatment enhances glioma cell susceptibility to TMZ by inhibiting the PI3K/AKT/mTOR pathway. As hyperactivation of the PI3K/AKT/mTOR pathway is frequently observed in gliomas, the combined use of ERβ agonists may become a feasible therapy option to overcome chemoresistance to TMZ.

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1	Lacroix M, Abi-Said D, Fourney DR, et al: A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 95:190–198. 2001. View Article : Google Scholar
2	Kanu OO, Hughes B, Di C, et al: Glioblastoma multiforme oncogenomics and signaling pathways. Clin Med Oncol. 3:39–52. 2009.PubMed/NCBI
3	Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
4	Minniti G, Salvati M, Arcella A, et al: Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neurooncol. 102:311–316. 2011. View Article : Google Scholar
5	Watanabe R, Nakasu Y, Tashiro H, et al: O6-methylguanine DNA methyltransferase expression in tumor cells predicts outcome of radiotherapy plus concomitant and adjuvant temozolomide therapy in patients with primary glioblastoma. Brain Tumor Pathol. 28:127–135. 2011. View Article : Google Scholar : PubMed/NCBI
6	Yin S, Yang J, Lin B, et al: Exome sequencing identifies frequent mutation of MLL2 in non-small cell lung carcinoma from Chinese patients. Sci Rep. 4:60362014. View Article : Google Scholar : PubMed/NCBI
7	Leung YK, Mak P, Hassan S and Ho SM: Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc Natl Acad Sci USA. 103:13162–13167. 2006. View Article : Google Scholar : PubMed/NCBI
8	Burns KA and Korach KS: Estrogen receptors and human disease: an update. Arch Toxicol. 86:1491–1504. 2012. View Article : Google Scholar : PubMed/NCBI
9	Li LC, Yeh CC, Nojima D and Dahiya R: Cloning and characterization of human estrogen receptor beta promoter. Biochem Biophys Res Commun. 275:682–689. 2000. View Article : Google Scholar : PubMed/NCBI
10	Roepke TA, Ronnekleiv OK and Kelly MJ: Physiological consequences of membrane-initiated estrogen signaling in the brain. Front Biosci (Landmark Ed). 16:1560–1573. 2011. View Article : Google Scholar :
11	Liu MM, Albanese C, Anderson CM, et al: Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem. 277:24353–24360. 2002. View Article : Google Scholar : PubMed/NCBI
12	Bailey ST, Shin H, Westerling T, Liu XS and Brown M: Estrogen receptor prevents p53-dependent apoptosis in breast cancer. Proc Natl Acad Sci USA. 109:18060–18065. 2012. View Article : Google Scholar : PubMed/NCBI
13	Nilsson S and Gustafsson JA: Estrogen receptors: therapies targeted to receptor subtypes. Clin Pharmacol Ther. 89:44–55. 2011. View Article : Google Scholar
14	Paruthiyil S, Cvoro A, Zhao X, et al: Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists. PLoS One. 4:e62712009. View Article : Google Scholar : PubMed/NCBI
15	Suzuki F, Akahira J, Miura I, et al: Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5′-untranslated region in human epithelial ovarian carcinoma. Cancer Sci. 99:2365–2372. 2008. View Article : Google Scholar : PubMed/NCBI
16	Mersereau JE, Levy N, Staub RE, et al: Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol. 283:49–57. 2008. View Article : Google Scholar : PubMed/NCBI
17	Kim YW, Zhao RJ, Park SJ, et al: Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production. Br J Pharmacol. 154:165–173. 2008. View Article : Google Scholar : PubMed/NCBI
18	Yang EJ, Park GH and Song KS: Neuroprotective effects of liquiritigenin isolated from licorice roots on glutamate-induced apoptosis in hippocampal neuronal cells. Neurotoxicology. 39:114–123. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhou M, Higo H and Cai Y: Inhibition of hepatoma 22 tumor by Liquiritigenin. Phytother Res. 24:827–833. 2010.
20	Sareddy GR, Nair BC, Gonugunta VK, et al: Therapeutic significance of estrogen receptor beta agonists in gliomas. Mol Cancer Ther. 11:1174–1182. 2012. View Article : Google Scholar : PubMed/NCBI
21	Ryu CH, Yoon WS, Park KY, et al: Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells. J Biomed Biotechnol. 2012:9874952012. View Article : Google Scholar : PubMed/NCBI
22	Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lakins J and Lupu R: Expression and regulation of estrogen receptor beta in human breast tumors and cell lines. Oncol Rep. 7:157–167. 2000.
23	Hennessy BT, Smith DL, Ram PT, Lu Y and Mills GB: Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 4:988–1004. 2005. View Article : Google Scholar : PubMed/NCBI
24	Shaw RJ and Cantley LC: Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 441:424–430. 2006. View Article : Google Scholar : PubMed/NCBI
25	Yin S, Wang P, Deng W, et al: Dosage compensation on the active X chromosome minimizes transcriptional noise of X-linked genes in mammals. Genome Biol. 10:R742009. View Article : Google Scholar : PubMed/NCBI
26	Yin S, Deng W, Hu L and Kong X: The impact of nucleosome positioning on the organization of replication origins in eukaryotes. Biochem Biophys Res Commun. 385:363–368. 2009. View Article : Google Scholar : PubMed/NCBI
27	Li W, Winters A, Poteet E, et al: Involvement of estrogen receptor beta5 in the progression of glioma. Brain Res. 1503:97–107. 2013. View Article : Google Scholar : PubMed/NCBI
28	Lindberg K, Helguero LA, Omoto Y, Gustafsson JA and Haldosen LA: Estrogen receptor beta represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: implications for tamoxifen sensitivity. Breast Cancer Res. 13:R432011. View Article : Google Scholar
29	Dai C, Zhang B, Liu X, et al: Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice. Endocrinology. 154:1247–1259. 2013. View Article : Google Scholar : PubMed/NCBI
30	Myers MG Jr, Grammer TC, Wang LM, et al: Insulin receptor substrate-1 mediates phosphatidylinositol 3′-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. J Biol Chem. 269:28783–28789. 1994.PubMed/NCBI
31	Jiang BH and Liu LZ: Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat. 11:63–76. 2008. View Article : Google Scholar : PubMed/NCBI
32	Deng WJ, Nie S, Dai J, Wu JR and Zeng R: Proteome, phosphoproteome, and hydroxyproteome of liver mitochondria in diabetic rats at early pathogenic stages. Mol Cell Proteomics. 9:100–116. 2010. View Article : Google Scholar :
33	Gaspar N, Marshall L, Perryman L, et al: MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature. Cancer Res. 70:9243–9252. 2010. View Article : Google Scholar : PubMed/NCBI
34	Toulany M, Lee KJ, Fattah KR, et al: Akt promotes post-irradiation survival of human tumor cells through initiation, progression, and termination of DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Res. 10:945–957. 2012. View Article : Google Scholar : PubMed/NCBI
35	Chock KL, Allison JM, Shimizu Y and ElShamy WM: BRCA1-IRIS overexpression promotes cisplatin resistance in ovarian cancer cells. Cancer Res. 70:8782–8791. 2010. View Article : Google Scholar : PubMed/NCBI
36	O’Brien NA, Browne BC, Chow L, et al: Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 9:1489–1502. 2010. View Article : Google Scholar
37	Xu J, Zhou JY, Wei WZ and Wu GS: Activation of the Akt survival pathway contributes to TRAIL resistance in cancer cells. PLoS One. 5:e102262010. View Article : Google Scholar : PubMed/NCBI
38	Wang SI, Puc J, Li J, et al: Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57:4183–4186. 1997.PubMed/NCBI