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.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 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.

Search
Journal information
Impact Factor


CiteScore 2018: 1.27

SCImago Journal Rank (SJR) 2018: 0.411
Source Normalized Impact per Paper (SNIP) 2018: 0.441

Cited By
Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 508 304 19
PDF Downloads 217 150 7