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2016 | 3 | 1 |

Article title

Inhibition of IRE1 signaling affects expression of a
subset genes encoding for TNF-related factors and
receptors and modifies their hypoxic regulation in
U87 glioma cells


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Inhibition of IRE1 (inositol requiring enzyme-1),
the major signaling pathway of endoplasmic reticulum
stress, significantly decreases tumor growth and
proliferation of glioma cells. To elucidate the role of IRE1-
mediated glioma growth, we studied the expression of a
subset genes encoding for TNF (tumor necrosis factor)-
related factors and receptors and their hypoxic regulation
in U87 glioma cells overexpressing dominant-negative
IRE1 (dnIRE1). We demonstrated that the expression of
and LITAF genes is increased in glioma cells with modified
IRE1; however, TNFRSF10B, TRADD, and TNFAIP3 is
down-regulated in these cells as compared to their control
counterparts. We did not find TNFRSF1A gene expression
to change significantly under this experimental condition.
In control glioma cells, hypoxia leads to the up-regulated
expression of TNFAIP1, TNFAIP3, TRADD, and TNFRSF10D
genes and the concomitant down-regulation of TNFRSF21,
TNFRSF11B, and LITAF genes; while, TNFRSF10B and
TNFRSF1A genes are resistant to hypoxic treatment.
However, inhibition of IRE1 modifies the hypoxic
regulation of LITAF, TNFRSF21, TNFRSF11B, and TRADD
genes and introduces hypoxia-induced sensitivity to TNFRSF10B, TNFRSF1A, and TNFSF7 gene expressions.
Furthermore, knockdown by siRNA of TNFRSF21 mRNA
modifies the hypoxic effect on the IRE1-dependent rate
of proliferation and cell death in U87 glioma cells. The
present study demonstrates that fine-tuned manipulation
of the expression of TNF-related factors and receptors
directly relating to cell death and proliferation, is mediated
by an effector of endoplasmic reticulum stress, IRE1,
as well as by hypoxia in a gene-specific manner. Thus,
inhibition of the kinase and endoribonuclease activities
of IRE1 correlates with deregulation of TNF-related factors
and receptors in a manner that is gene specific and thus
slows tumor growth.







Physical description


11 - 2 - 2016
13 - 7 - 2015
9 - 12 - 2015


  • Department of Molecular Biology, Palladin Institute
    of Biochemistry National Academy of Sciences of Ukraine, 9
    Leontovycha St., 01601, Kyiv, Ukraine
  • Department of Molecular Biology, Palladin Institute
    of Biochemistry National Academy of Sciences of Ukraine, 9
    Leontovycha St., 01601, Kyiv, Ukraine
  • Department of Molecular Biology, Palladin Institute
    of Biochemistry National Academy of Sciences of Ukraine, 9
    Leontovycha St., 01601, Kyiv, Ukraine
  • Departments of Pediatrics, Bohomolets
    National Medical University, 13 Shevchenka Blvd., 01601, Kyiv,
  • Department of Molecular Biology, Palladin Institute
    of Biochemistry National Academy of Sciences of Ukraine, 9
    Leontovycha St., 01601, Kyiv, Ukraine
  • Department of Molecular Biology, Palladin Institute
    of Biochemistry National Academy of Sciences of Ukraine, 9
    Leontovycha St., 01601, Kyiv, Ukraine


  • [1] Zhang K, Kaufman RJ. The unfolded protein response: a stresssignaling pathway critical for health and disease. Neurology2006; 66 (Suppl 1): S102–9.[Crossref]
  • [2] Moenner M, Pluquet O, Bouchecareilh M, Chevet E. Integratedendoplasmic reticulum stress responses in cancer. Cancer Res2007; 67: 10631–4.[WoS][Crossref]
  • [3] Wang S, Kaufman RJ. The impact of the unfolded proteinresponse on human disease. J Cell Biol 2012; 197: 857-67.
  • [4] Pluquet O, Dejeans N, Chevet E. Watching the clock:endoplasmic reticulum-mediated control of circadian rhythmsin cancer. Ann Med 2014; 46: 233-43.[WoS][Crossref]
  • [5] Chesney J, Clark J, Klarer AC, Imbert-Fernandez Y, LaneAN, Telang S. Fructose-2,6-bisphosphate synthesis by6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4) is required for the glycolytic response to hypoxia andtumor growth. Oncotarget 2014; 5: 6670-86.[Crossref]
  • [6] Manié SN, Lebeau J, Chevet E. Cellular mechanisms ofendoplasmic reticulum stress signaling in health and disease.3. Orchestrating the unfolded protein response in oncogenesis:an update. Am J Physiol Cell Physiol 2014; 307: C901-7.[WoS]
  • [7] Malhotra JD, Kaufman RJ. ER stress and its functional link tomitochondria: role in cell survival and death. Cold Spring HarbPerspect Biol 2011; 3: a004424.[WoS]
  • [8] Lenihan CR, Taylor CT. The impact of hypoxia on cell deathpathways. Biochem Soc Trans 2013; 41: 657–63.[Crossref][WoS]
  • [9] Hetz C, Chevet E, Harding HP. Targeting the unfolded proteinresponse in disease. Nat Rev Drug Discov 2013; 12: 703-19.[WoS][Crossref]
  • [10] Auf G, Jabouille A, Delugin M, Guérit S, Pineau R, North S,Platonova N, Maitre M, Favereaux A, Vajkoczy P, Seno M,Bikfalvi A, Minchenko D, Minchenko O, Moenner M. Highepiregulin expression in human U87 glioma cells relieson IRE1alpha and promotes autocrine growth through EGFreceptor. BMC Cancer 2013; 13: 597.[Crossref][WoS]
  • [11] Pluquet O, Dejeans N, Bouchecareilh M, Lhomond S, Pineau R,Higa A, Delugin M, Combe C, Loriot S, Cubel G, Dugot-SenantN, Vital A, Loiseau H, Gosline SJ, Taouji S, Hallett M, SarkariaJN, Anderson K, Wu W, Rodriguez FJ, Rosenbaum J, Saltel F,Fernandez-Zapico ME, Chevet E. Posttranscriptional regulationof PER1 underlies the oncogenic function of IREα. Cancer Res.2013; 73: 4732–43.[WoS][Crossref]
  • [12] Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, AriasC, Lennon CJ, Kluger Y, Dynlacht DD. XBP1 controls diversecell type- and condition-specific transcriptional regulatorynetworks. Molecular Cell 2007; 27: 53–66.[Crossref][WoS]
  • [13] Aragón T, van Anken E, Pincus D., Serafimova IM, Korennykh AV,Rubio CA, Walter P. Messenger RNA targeting to endoplasmicreticulum stress signalling sites. Nature. 2009; 457: 736–40.[WoS]
  • [14] Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, PineauR, Nalbantoglu J, Kaufman RJ, Chevet E, Bikfalvi A, MoennerM. IRE1 signaling is essential for ischemia-induced vascularendothelial growth factor-A expression and contributes toangiogenesis and tumor growth in vivo. Cancer Res 2007; 67:6700–7.[Crossref]
  • [15] Auf G, Jabouille A, Guerit S, Pineau R, Delugin M, BouchecareilhM, Magnin N, Favereaux A, Maitre M, Gaiser T, von DeimlingA, Czabanka M, Vajkoczy P, Chevet E, Bikfalvi A, MoennerM. Inositol-requiring enzyme 1alpha is a key regulator ofangiogenesis and invasion in malignant glioma. Proc Natl AcadSci USA 2010; 107: 15553–8.
  • [16] Cullen SP, Martin SJ. Fas and TRAIL ‘death receptors’ asinitiators of inflammation: Implications for cancer. Semin CellDev Biol 2015; 39: 26-34.[Crossref][WoS]
  • [17] Benschop R, Wei T, Na S. Tumor necrosis factor receptorsuperfamily member 21: TNFR-related death receptor-6, DR6.Adv Exp Med Biol 2009; 647: 186-94.
  • [18] Fares F, Azzam N, Fares B, Larsen S, Lindkaer-Jensen S.Benzene-poly-carboxylic acid complex, a novel anti-canceragent induces apoptosis in human breast cancer cells. PLoSOne 2014; 9: e85156.[WoS][Crossref]
  • [19] Mirzaei MR, Najafi A, Arababadi MK, Asadi MH, Mowla SJ.Altered expression of apoptotic genes in response to OCT4B1suppression in human tumor cell lines. Tumour Biol 2014; 35:9999-10009.[Crossref]
  • [20] Hu R, Du Q, Yin X, Li J, Wang T and Zhang L. Agonist antibodyactivates death receptor 6 downstream signaling involvingTRADD recruitment. FEBS Lett 2014; 588: 401-7.[WoS]
  • [21] Zeng L, Li T, Xu DC, Liu J, Mao G, Cui MZ, Fu X and Xu X. Deathreceptor 6 induces apoptosis not through type I or type IIpathways, but via a unique mitochondria-dependent pathwayby interacting with Bax protein. J Biol Chem 2012; 287:29125-33.
  • [22] Haselmann V, Kurz A, Bertsch U, Hubner S, Olempska-MullerM, Fritsch J, Hasler R, Pickl A, Fritsche H, Annewanter F, EnglerC, Fleig B, Bernt A, Roder C, Schmidt H, Gelhaus C, Hauser C,Egberts JH, Heneweer C, Rohde AM, Boger C, Knippschild U,Rocken C, Adam D, Walczak H, Schutze S, Janssen O, WulczynFG, Wajant H, Kalthoff H, Trauzold A. Nuclear death receptorTRAIL-R2 inhibits maturation of let-7 and promotes proliferationof pancreatic and other tumor cells. Gastroenterology 2014;146: 278-90.
  • [23] Li T, Su L, Lei Y, Liu X, Zhang Y, Liu X. DDIT3 and KAT2A proteinsregulate TNFRSF10A and TNFRSF10B expression in endoplasmicreticulum stress-mediated apoptosis in human lung cancercells. J Biol Chem 2015; 290: 11108-18.
  • [24] Sarhan D, D’Arcy P, Lundqvist A. Regulation of TRAIL-receptorexpression by the ubiquitin-proteasome system. Int J Mol Sci2014; 15: 18557-73.[Crossref]
  • [25] von Karstedt S, Conti A, Nobis M, Montinaro A, Hartwig T,Lemke J, Legler K, Annewanter F, Campbell AD, Taraborrelli L,Grosse-Wilde A, Coy JF, El-Bahrawy MA, Bergmann F, Koschny R,Werner J, Ganten TM, Schweiger T, Hoetzenecker K, KenesseyI, Hegedüs B, Bergmann M, Hauser C, Egberts JH, Becker T,Röcken C, Kalthoff H, Trauzold A, Anderson KI, Sansom OJ,Walczak H. Cancer cell-autonomous TRAIL-R signaling promotesKRAS-driven cancer progression, invasion, and metastasis.Cancer Cell 2015; 27: 561-73.[WoS][Crossref]
  • [26] Inoue M, Kamada H, Abe Y, Higashisaka K, Nagano K, Mukai Y,Yoshioka Y, Tsutsumi Y, Tsunoda S. Aminopeptidase P3, a newmember of the TNF-TNFR2 signaling complex, induces phosphorylationof JNK1 and JNK2. J Cell Sci. 2015; 128: 656-69.
  • [27] Shukla K, Sharma AK, Ward A, Will R, Hielscher T, Balwierz A,Breunig C, Münstermann E, König R, Keklikoglou I, Wiemann S.MicroRNA-30c-2-3p negatively regulates NF-κB signaling andcell cycle progression through down-regulation of TRADD andCCNE1 in breast cancer. Mol Oncol 2015; 9: 1106-19.[WoS][Crossref]
  • [28] Trebing J, El-Mesery M, Schäfer V, Weisenberger D, SiegmundD, Silence K, Wajant H. CD70-restricted specific activation ofTRAILR1 or TRAILR2 using scFv-targeted TRAIL mutants. CellDeath Dis. 2014 ; 5: e1035.
  • [29] Yoshino K, Kishibe K, Nagato T, Ueda S, Komabayashi Y,Takahara M, Harabuchi Y. Expression of CD70 in nasal naturalkiller/T cell lymphoma cell lines and patients; its role for cellproliferation through binding to soluble CD27. Br J Haematol2013; 160: 331-42.
  • [30] Zhang X, Li X, Tan Z, Liu X, Yang C, Ding X, Hu X, Zhou J, XiangS, Zhou C, Zhang J. MicroRNA-373 is up-regulated and targetsTNFAIP1 in human gastric cancer, contributing to tumorigenesis.Oncol Lett 2013; 6: 1427-34.
  • [31] Kim DM, Chung KS, Choi SJ, Jung YJ, Park SK, Han GH, Ha JS,Song KB, Choi NS, Kim HM, Won M, Seo YS. RhoB inducesapoptosis via direct interaction with TNFAIP1 in HeLa cells. Int JCancer 2009; 125: 2520-7.
  • [32] da Silva CG, Minussi DC, Ferran C, Bredel M. A20 expressingtumors and anticancer drug resistance. Adv Exp Med Biol 2014;809: 65-81.
  • [33] Liu J, Yang S, Wang Z, Chen X, Zhang Z. Ubiquitin ligase A20regulates p53 protein in human colon epithelial cells. J BiomedSci 2013; 20: 74.
  • [34] Bertolo C, Roa S, Sagardoy A, Mena-Varas M, Robles EF,Martinez-Ferrandis JI, Sagaert X, Tousseyn T, Orta A, LossosIS, Amar S, Natkunam Y, Briones J, Melnick A, MalumbresR, Martinez-Climent JA. LITAF, a BCL6 target gene, regulatesautophagy in mature B-cell Lymphomas. Br J Haematol 2013;162: 621-30.[WoS]
  • [35] Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B. A modelfor p53-induced apoptosis. Nature 1997; 389: 300-5.
  • [36] Minchenko DO, Danilovskyi SV, Kryvdiuk IV, Bakalets TV, LypovaNM, Karbovskyi LL, Minchenko OH. Inhibition of ERN1 modifiesthe hypoxic regulation of the expression of TP53-related genesin U87 glioma cells. Endoplasm Reticul Stress Dis 2014; 1:18-26.
  • [37] Bochkov VN, Philippova M, Oskolkova O, Kadl A, FurnkranzA, Karabeg E, Breuss J, Minchenko OH, Mechtcheriakova D,Hohensinner P, Rychli K, Wojta J, Resink T, Binder BR, LeitingerN. Oxidized phospholipids stimulate angiogenesis viainduction of VEGF, IL-8, COX-2 and ADAMTS-1 metalloprotease,implicating a novel role for lipid oxidation in progression anddestabilization of atherosclerotic lesions. Circ Res 2006; 99:900-8.
  • [38] Minchenko O.H., Tsymbal D.O., Moenner M., Minchenko D.O.,Kovalevska O.V., Lypova N.M. Inhibition of the endoribonucleaseof ERN1 signaling enzyme affects the expression ofproliferation-related genes in U87 glioma cells. EndoplasmReticul Stress Dis 2015; 2: 18-29.
  • [39] Jang,J.Y., Jeon,Y.K., Choi,Y. and Kim,C.W. Short-hairpinRNA-induced suppression of adenine nucleotide translocase-2in breast cancer cells restores their susceptibility to TRAILinducedapoptosis by activating JNK and modulating TRAILreceptor expression. Mol Cancer 2010; 9: 262.[Crossref][WoS]
  • [40] Venza M, Visalli M, Catalano T, Fortunato C, Oteri R, Teti D andVenza I. Impact of DNA methyltransferases on the epigeneticregulation of tumor necrosis factor-related apoptosis-inducingligand (TRAIL) receptor expression in malignant melanoma.Biochem Biophys Res Commun 2013; 441: 743-50.
  • [41] Ratzinger G, Mitteregger S, Wolf B, Berger R, Zelger B, WeinlichG, Fritsch P, Goebel G, Fiegl H. Association of TNFRSF10DDNA-methylation with the survival of melanoma patients. Int JMol Sci 2014; 15: 11984-95.[Crossref][WoS]
  • [42] Tian,X., Ye,J., Alonso-Basanta,M., Hahn,S.M., Koumenis,C.and Dorsey,J.F. Modulation of CCAAT/enhancer binding proteinhomologous protein (CHOP)-dependent DR5 expression bynelfinavir sensitizes glioblastoma multiforme cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J BiolChem 2011; 286: 29408-16.[WoS]
  • [43] Ciechomska IA, Gabrusiewicz K, Szczepankiewicz AA,Kaminska B. Endoplasmic reticulum stress triggers autophagyin malignant glioma cells undergoing cyclosporine a-inducedcell death. Oncogene 2013; 32: 1518-29.[Crossref][WoS]
  • [44] Denko NC. Hypoxia, HIF1 and glucose metabolism in the solidtumour. Nat Rev Cancer 2008; 8: 705-13.[Crossref][WoS]
  • [45] Minchenko OH, Tsymbal DO, Minchenko DO, Kovalevska OV,Karbovskyi LL, Bikfalvi A. Inhibition of ERN1 signaling enzymeaffects hypoxic regulation of the expression of E2F8, EPAS1,HOXC6, ATF3, TBX3 and FOXF1 genes in U87 glioma cells. UkrBiochem J 2015; 87(2): 76-87.[Crossref]
  • [46] Backer MV, Backer JM, Chinnaiyan P. Targeting the unfoldedprotein response in cancer therapy. Methods Enzymol. 2011;491: 37–56.[WoS]
  • [47] Johnson GG, White MC, Grimaldi M. Stressed to death:targeting endoplasmic reticulum stress response inducedapoptosis in gliomas. Curr Pharm Des. 2011; 17: 284-92.[Crossref]
  • [48] Danilovskyi S.V., Minchenko D.O., Karbovskyi L.L., O.S.Moliavko, Kovalevska O.V., Minchenko O.H. ERN1 knockdownmodifies the hypoxic regulation of TP53, MDM2, USP7 and PERPgene expressions in U87 glioma cells. Ukr Biochem J 2014; 86:90-102.

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