Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

Open access

Abstract

Objective. The aim of the present study was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoded estrogen related proteins (NRIP1/RIP140, TRIM16/EBBP, ESRRA/NR3B1, FAM162A/E2IG5, PGRMC2/PMBP, and SLC39A6/LIV-1) and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of glioma cells proliferation.

Methods. The expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by a quantitative polymerase chain reaction.

Results. Inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 signaling enzyme function up-regulates the expression of EBBP, E2IG5, PGRMC2, and SLC39A6 genes is in U87 glioma cells in comparison with the control glioma cells, with more significant changes for E2IG5 and PGRMC2 genes. At the same time, the expression of NRIP1 and ESRRA genes is strongly down-regulated in glioma cells upon inhibition of IRE1. We also showed that hypoxia increases the expression of E2IG5, PGRMC2, and EBBP genes and decreases NRIP1 and ESRRA genes expression in control glioma cells. Furthermore, the inhibition of IRE1 in U87 glioma cells decreases the eff ect of hypoxia on the expression of E2IG5 and PGRMC2 genes, eliminates hypoxic regulation of NRIP1 gene, and enhances the sensitivity of ESRRA gene to hypoxic condition. Furthermore, the expression of SLC39A6 gene is resistant to hypoxia in both the glioma cells with and without IRE1 signaling enzyme function.

Conclusions. Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function affects the expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells in gene specific manner and these changes possibly contribute to the suppression of the cell proliferation. Most of these genes are regulated by hypoxia and preferentially through IRE1 signaling pathway of endoplasmic reticulum stress.

Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD. XBP1 controls diverse cell type- and condition-specifi c transcriptional regulatory networks. Mol Cell 27, 53-66, 2007.

Aragon T, van Anken E, Pincus D, Serafi mova IM, Korennykh AV, Rubio CA, Walter P. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 457, 736-740, 2009.

Auf G, Jabouille A, Guerit S, Pineau R, Delugin M, Bouchecareilh M, Favereaux A, Maitre M, Gaiser T, von Deimling A, Czabanka M, Vajkoczy P, Chevet E, Bikfalvi A, Moenner M. A shift from an angiogenic to invasive phenotype induced in malignant glioma by inhibition of the unfolded protein response sensor IRE1. Proc Natl Acad Sci U S A 107, 15553-15558, 2010.

Auf G, Jabouille A, Delugin M, Guerit S, Pineau R, North S, Platonova N, Maitre M, Favereaux A, Vajkoczy P, Seno M, Bikfalvi A, Minchenko D, Minchenko O, Moenner M. High epiregulin expression in human U87 glioma cells relies on IRE1alpha and promotes autocrine growth through EGF receptor. BMC Cancer 13, 597, 2013.

Aziz MH, Chen X, Zhang Q, DeFrain C, Osland J, Luo Y, Shi X, Yuan R. Suppressing NRIP1 inhibits growth of breast cancer cells in vitro and in vivo. Oncotarget 6, 39714-39724, 2015.

Bell JL, Malyukova A, Kavallaris M, Marshall GM, Cheung BB. TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization. Cell Cycle 12, 889-898, 2013.

Bochkov VN, Philippova M, Oskolkova O, Kadl A, Furnkranz A, Karabeg E, Breuss J, Minchenko OH, Mechtcheriakova D, Hohensinner P, Rychli K, Wojta J, Resink T, Binder BR, Leitinger N. Oxidized phospholipids stimulate angiogenesis via induction of VEGF, IL-8, COX-2 and ADAMTS-1 metalloprotease, implicating a novel role for lipid oxidation in progression and destabilization of atherosclerotic lesions. Circ Res 99, 900-908, 2006.

Casaburi I, Avena P, De Luca A, Chimento A, Sirianni R, Malivindi R, Rago V, Fiorillo M, Domanico F, Campana C, Cappello AR, Sotgia F, Lisanti MP, Pezzi V. Estrogen related receptor alpha (ERRalpha) a promising target for the therapy of adrenocortical carcinoma (ACC). Oncotarget 6, 25135-25148, 2015.

Chevet E, Hetz C, Samali A. Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov 5, 586-597, 2015.

Cho YE, Kim JY, Kim YW, Park JH, Lee S. Expression and prognostic signifi cance of human growth and transformation- dependent protein in gastric carcinoma and gastric adenoma. Hum Pathol 40, 975-981, 2009.

Cho YE, Kim JY, Kim YJ, Kim YW, Lee S, Park JH. Expression and clinicopathological signifi cance of human growth and transformation-dependent protein (HGTD-P) in uterine cervical cancer. Histopathology 57, 479-482, 2010.

Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell 25, 563-573, 2014.

Cookman CJ, Belcher SM. Estrogen receptor-β Up-regulates IGF1R rxpression and activity to inhibit apoptosis and increase growth of medulloblastoma. Endocrinology 156, 2395-2408, 2015.

Dejeans N, Pluquet O, Lhomond S, Grise F, Bouchecareilh M, Juin A, Meynard-Cadars M, Bidaud-Meynard A, Gentil C, Moreau V, Saltel F, Chevet E. Autocrine control of glioma cells adhesion and migration through IRE1a-mediated cleavage of SPARC mRNA. J Cell Sci 125, 4278-4287, 2012.

Dejeans N, Barroso K, Fernandez-Zapico ME, Samali A, Chevet E. Novel roles of the unfolded protein response in the control of tumor development and aggressiveness. Semin Cancer Biol 33, 67-73, 2015.

De Luca A, Fiorillo M, Peiris-Pages M, Ozsvari B, Smith DL, Sanchez-Alvarez R, Martinez-Outschoorn UE, Cappello AR, Pezzi V, Lisanti MP, Sotgia F. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget 6, 14777-14795, 2015.

Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu J, Kaufman RJ, Chevet E, Bikfalvi A, Moenner M. IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res 67, 6700-6707, 2007.

Gibson WJ, Hoivik EA, Halle MK, Taylor-Weiner A, Cherniack AD, Berg A, Holst F, Zack TI, Werner HM, Staby KM, Rosenberg M, Stefansson IM, Kusonmano K, Chevalier A, Mauland KK, Trovik J, Krakstad C, Giannakis M, Hodis E, Woie K, Bjorge L, Vintermyr OK, Wala JA, Lawrence MS, Getz G, Carter SL, Beroukhim R, Salvesen HB. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat Genet 48, 848-855, 2016.

Hamidian A, von Stedingk K, Munksgaard Th oren M, Mohlin S, Pahlman S. Diff erential regulation of HIF-1alpha and HIF-2alpha in neuroblastoma: Estrogen-related receptor alpha (ERRalpha) regulates HIF2A transcription and correlates to poor outcome. Biochem Biophys Res Commun 461, 560-567, 2015.

Kim JH, Jeong IY, Lim Y, Lee YH, Shin SY. Estrogen receptor beta stimulates Egr-1 transcription via MEK1/Erk/Elk-1 cascade in C6 glioma cells. BMB Rep 44, 452-457, 2011.

Kim PY, Rahmanto AS, Tan O, Norris MD, Haber M, Marshall GM, Cheung BB. TRIM16 overexpression induces apoptosis through activation of caspase-2 in cancer cells. Apoptosis 18, 639-651, 2013.

Kim PY, Tan O, Liu B, Trahair T, Liu T, Haber M, Norris MD, Marshall GM, Cheung BB. High TDP43 expression is required for TRIM16-induced inhibition of cancer cell growth and correlated with good prognosis of neuroblastoma and breast cancer patients. Cancer Lett 374, 315-323, 2016.

Lapierre M, Docquier A, Castet-Nicolas A, Gitenay D, Jalaguier S, Teyssier C, Cavailles V. Th e emerging role of the transcriptional coregulator RIP140 in solid tumors. Biochim Biophys Acta 1856, 144-150, 2015.

Lau KM, To KF. Importance of estrogenic signaling and its mediated receptors in prostate cancer. Int J Mol Sci 17, pii: E1434, 2016.

Lee MJ, Kim JY, Suk K, Park JH. Identifi cation of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway. Mol Cell Biol 24, 3918-3927, 2004.

Lenihan CR, Taylor CT. Th e impact of hypoxia on cell death pathways. Biochem Soc Trans 41, 657-663, 2013.

Li W, Winters A, Poteet E, Ryou MG, Lin S, Hao S, Wu Z, Yuan F, Hatanpaa KJ, Simpkins JW, Yang SH. Involvement of estrogen receptor β5 in the progression of glioma. Brain Res 1503, 97-107, 2013.

Li L, Dong L, Qu X, Jin S, Lv X, Tan G. Tripartite motif 16 inhibits hepatocellular carcinoma cell migration and invasion. Int J Oncol 48, 1639-1649, 2016.

Lian J, Jing Y, Dong Q, Huan L, Chen D, Bao C, Wang Q, Zhao F, Li J, Yao M, Qin L, Liang L, He X. miR-192, a prognostic indicator, targets the SLC39A6/SNAIL pathway to reduce tumor metastasis in human hepatocellular carcinoma. Oncotarget 7, 2672-2683, 2016.

Manie SN, Lebeau J, Chevet E. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 3. Orchestrating the unfolded protein response in oncogenesis: an update. Am J Physiol Cell Physiol 307, C901-C907, 2014.

Matsushima H, Mori T, Ito F, Yamamoto T, Akiyama M, Kokabu T, Yoriki K, Umemura S, Akashi K, Kitawaki J. Anti-tumor eff ect of estrogen-related receptor alpha knockdown on uterine endometrial cancer. Oncotarget 7, 34131-34148, 2016.

Maurel M, Chevet E, Tavernier J, Gerlo S. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci 39, 245-254, 2014.

Maurel M, McGrath EP, Mnich K, Healy S, Chevet E, Samali A. Controlling the unfolded protein response-mediated life and death decisions in cancer. Semin Cancer Biol 33, 57-66, 2015.

Minchenko DO, Kharkova AP, Tsymbal DO, Karbovskyi LL, Minchenko OH. Expression of insulin-like growth factor binding protein genes and its hypoxic regulation in U87 glioma cells depends on ERN1 mediated signaling pathway of endoplasmic reticulum stress. Endocr Regul 49, 73-83, 2015.

Mueller MD, Vigne JL, Minchenko AG, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA 97, 10972-10977, 2000.

Pedram A, Razandi M, Wallace DC, Levin ER. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 17, 2125-2137, 2006.

Petersen SL, Intlekofer KA, Moura-Conlon PJ, Brewer DN, Del Pino Sans J, Lopez JA. Novel progesterone receptors: neural localization and possible functions. Front Neurosci 7, 164, 2013.

Pluquet O, Dejeans N, Bouchecareilh M, Lhomond S, Pineau R, Higa A, Delugin M, Combe C, Loriot S, Cubel G, Dugot-Senant N, Vital A, Loiseau H, Gosline SJ, Taouji S, Hallett M, Sarkaria JN, Anderson K, Wu W, Rodriguez FJ, Rosenbaum J, Saltel F, Fernandez-Zapico ME, Chevet E. Posttranscriptional regulation of PER1 underlies the oncogenic function of IREα. Cancer Res 73, 4732-4743, 2013.

Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. Ann Med 46, 233-243, 2014.

Rajapaksa G, Th omas C, Gustafsson JA. Estrogen signaling and unfolded protein response in breast cancer. J Steroid Biochem Mol Biol 163, 45-50, 2016.

Ranhotra HS. Estrogen-related receptor alpha and cancer: axis of evil. J Recept Signal Transduct Res 35, 505-508, 2015.

Rohatgi N, Matta A, Kaur J, Srivastava A, Ralhan R. Novel molecular targets of smokeless tobacco (khaini) in cell culture from oral hyperplasia. Toxicology 224, 1-13, 2006.

Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, Wang YC, Duran GE, Sikic TL, Caldeira S, Skomedal H, Tu IP, Hernandez-Boussard T, Johnson SW, O’Dwyer PJ, Fero MJ, Kristensen GB, Borresen- Dale AL, Hastie T, Tibshirani R, van de Rijn M, Teng NN, Longacre TA, Botstein D, Brown PO, Sikic BI. Gene expression patterns in ovarian carcinomas. Mol Biol Cell 14, 4376-4386, 2003.

Sutton SK, Koach J, Tan O, Liu B, Carter DR, Wilmott JS, Yosufi B, Haydu LE, Mann GJ, Thompson JF, Long GV, Liu T, McArthur G, Zhang XD, Scolyer RA, Cheung BB, Marshall GM. TRIM16 inhibits proliferation and migration through regulation of interferon beta 1 in melanoma cells. Oncotarget 5, 10127-10139, 2014.

Takatani-Nakase T, Matsui C, Maeda S, Kawahara S, Takahashi K. High glucose level promotes migration behavior of breast cancer cells through zinc and its transporters. PLoS ONE 9, E90136, 2014.

Tavares CB, Gomes-Braga Fd, Costa-Silva DR, Escorcio-Dourado CS, Borges US, Conde-Junior AM, Barros-Oliveira Mda C, Sousa EB, Barros Lda R, Martins LM, Facina G, da-Silva BB. Expression of estrogen and progesterone receptors in astrocytomas: a literature review. Clinics (Sao Paulo) 71, 481-486, 2016.

Taylor KM, Muraina IA, Brethour D, Schmitt-Ulms G, Nimmanon T, Ziliotto S, Kille P, Hogstrand C. Zinc transporter ZIP10 forms a heteromer with ZIP6 which regulates embryonic development and cell migration. Biochem J 473, 2531-2544, 2016.

Tiwari A, Swamy S, Gopinath KS, Kumar A. Genomic amplifi cation upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo. Sci Rep 5, 17621, 2015.

Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA. A regulatory role for RIP140 in nuclear receptor activation. Mol Endocrinol 12, 864-881, 1998.

Ur Rahman MS, Cao J. Estrogen receptors in gastric cancer: Advances and perspectives. World J Gastroenterol 22, 2475-2482, 2016.

Wada J, Nakatsuka A. Mitochondrial dynamics and mitochondrial dysfunction in diabetes. Acta Med Okayama 70, 151-158, 2016.

Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol 5, 297-348, 2010.

Wang D, Liang J, Zhang Y, Gui B, Wang F, Yi X, Sun L, Yao Z, Shang Y. Steroid receptor coactivator-interacting protein (SIP) inhibits caspase-independent apoptosis by preventing apoptosis-inducing factor (AIF) from being released from mitochondria. J Biol Chem 287, 12612-12621, 2012.

Wendler A, Wehling M. PGRMC2, a yet uncharacterized protein with potential as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 enzyme activity. Steroids 78, 555-558, 2013.

Wesolowska M, Pawlik P, Jagodzinski PP. Th e clinicopathologic signifi cance of estrogen receptors in human gastric carcinoma. Biomed Pharmacother 83, 314-322, 2016.

Ye X, Zhang Y, He B, Meng Y, Li Y, Gao Y. Quantitative proteomic analysis identifi es new eff ectors of FOXM1 involved in breast cancer cell migration. Int J Clin Exp Pathol 8, 15836-15844, 2015.

Zhang LD, Chen L, Zhang M, Qi HJ, Chen L, Chen HF, Zhong MK, Shi XJ, Li QY. Downregulation of ERRα inhibits angiogenesis in human umbilical vein endothelial cells through regulating VEGF production and PI3K/Akt/STAT3 signaling pathway. Eur J Pharmacol 769, 167-176, 2015.

Zhu J, Zhuang T, Yang H, Li X, Liu H, Wang H. Atypical ubiquitin ligase RNF31: the nuclear factor modulator in breast cancer progression. BMC Cancer 16, 538, 2016.

Journal Information


CiteScore 2017: 1.35

SCImago Journal Rank (SJR) 2017: 0.450
Source Normalized Impact per Paper (SNIP) 2017: 0.424

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 208 208 42
PDF Downloads 68 68 16