Ukr.Biochem.J. 2013; Volume 85, Issue 5, Sep-Oct, pp. 5-16


Endoplasmic reticulum stress, its sensor and signalling systems and the role in regulation of gene expression at malignant tumor growth and hypoxia

O. H. Minchenko, A. P. Kharkova, T. V. Bakalets, I. V. Kryvdiuk

Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;

Hypoxia is one of the inductors of the expression of a large group of genes, which control glycolysis and proliferation processes in low oxygen conditions or as a result of low oxygen consumption. Moreover, hypoxia is one of the factors which induce the endoplasmic reticulum stress which, like hypoxia, is an obligatory component of malignant tumor growth and is connected with cytoplasm and nuclei through three sensor and signalling systems: PERK, ATF6 та ERN1. The suppression of ERN1, the main sensing and signalling enzyme of endoplasmic reticulum stress, leads to a decrease of tumor growth and changes the character of hypoxic regulation of many genes responsible for the control of proliferation and glycolysis. ERN1 sensing­ and signalling system controls the expression of a large set of genes, which are dependent on endoplasmic reticulum stress as well as hypoxia. Moreover, this signalling pathway is an important factor of malignant tumor growth.

Keywords: , , , , , , ,


  1. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002 Nov;110(10):1389-98. Review. PubMed, PubMedCentralCrossRef
  2.  Chakrabarti A, Chen AW, Varner JD. A review of the mammalian unfolded protein response. Biotechnol Bioeng. 2011 Dec;108(12):2777-93. Review. PubMed, PubMedCentral, CrossRef
  3. Shen X, Zhang K, Kaufman RJ. The unfolded protein response–a stress signaling pathway of the endoplasmic reticulum. J Chem Neuroanat. 2004 Sep;28(1-2):79-92. Review. PubMed, CrossRef
  4.  Wu J, Kaufman RJ. From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ. 2006 Mar;13(3):374-84. Review. PubMed, CrossRef
  5.  Hetz C, Glimcher LH. Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome. Mol Cell. 2009 Sep 11;35(5):551-61. Review. PubMed, PubMedCentral, CrossRef
  6. Luo D, He Y, Zhang H, Yu L, Chen H, Xu Z, Tang S, Urano F, Min W. AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response. J Biol Chem. 2008 May 2;283(18):11905-12.  PubMed, PubMedCentral, CrossRef
  7. Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, Imaizumi K. Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011 Feb 11;286(6):4809-18. PubMed, PubMedCentral, CrossRef
  8. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P. The unfolded protein response signals through high-order assembly of Ire1. Nature. 2009 Feb 5;457(7230):687-93. PubMed, PubMedCentral, CrossRef
  9. Badiola N, Penas C, Miñano-Molina A, Barneda-Zahonero B, Fadó R, Sánchez-Opazo G, Comella JX, Sabriá J, Zhu C, Blomgren K, Casas C, Rodríguez-Alvarez J. Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12. Cell Death Dis. 2011 Apr 28;2:e149. PubMed, PubMedCentral, CrossRef
  10. Woehlbier U, Hetz C. Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem Sci. 2011 Jun;36(6):329-37. Review. PubMed, CrossRef
  11. Park SW, Zhou Y, Lee J, Lee J, Ozcan U. Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci USA. 2010 Nov 9;107(45):19320-5. PubMed, PubMedCentral, CrossRef
  12. Schröder M. Endoplasmic reticulum stress responses. Cell Mol Life Sci. 2008 Mar;65(6):862-94. Review. PubMedCrossRef
  13. Aragón T, van Anken E, Pincus D, Serafimova IM, Korennykh AV, Rubio CA, Walter P. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature. 2009 Feb 5;457(7230):736-40. PubMed, PubMedCentral, CrossRef
  14. Liu CY, Kaufman RJ. The unfolded protein response. J Cell Sci. 2003 May 15;116(Pt 10):1861-2. Review. PubMedCrossRef
  15. Kaufman RJ, Back SH, Song B, Han J, Hassler J. The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:99-107. Review. PubMed, PubMedCentral, CrossRef
  16. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000 Jun;2(6):326-32. PubMedCrossRef
  17. Backer MV, Backer JM, Chinnaiyan P. Targeting the unfolded protein response in cancer therapy. Methods Enzymol. 2011;491:37-56. PubMed, CrossRef
  18. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol. 2004 Sep;24(17):7469-82. PubMed, PubMedCentralCrossRef
  19. Fels DR, Koumenis C. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther. 2006 Jul;5(7):723-8. Review. PubMed, CrossRef
  20. Lee SK, Kim YS. Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria. Int J Oncol. 2013 Mar;42(3):810-6. PubMedPubMedCentral, CrossRef
  21. Gentz SH, Bertollo CM, Souza-Fagundes EM, da Silva AM. Implication of eIF2α kinase GCN2 in induction of apoptosis and endoplasmic reticulum stress-responsive genes by sodium salicylate. J Pharm Pharmacol. 2013 Mar;65(3):430-40. PubMed, CrossRef
  22. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006 Oct;86(4):1133-49. Review. PubMed, CrossRef
  23. Cao J, Dai DL, Yao L, Yu HH, Ning B, Zhang Q, Chen J, Cheng WH, Shen W, Yang ZX. Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem. 2012 May;364(1-2):115-29. PubMed, CrossRef
  24. Wang M, Ye R, Barron E, Baumeister P, Mao C, Luo S, Fu Y, Luo B, Dubeau L, Hinton DR, Lee AS. Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis. Cell Death Differ. 2010 Mar;17(3):488-98. PubMed, PubMedCentral, CrossRef
  25. Farías M, Puebla C, Westermeier F, Jo MJ, Pastor-Anglada M, Casanello P, Sobrevia L. Nitric oxide reduces SLC29A1 promoter activity and adenosine transport involving transcription factor complex hCHOP-C/EBPalpha in human umbilical vein endothelial cells from gestational diabetes. Cardiovasc Res. 2010 Apr 1;86(1):45-54. PubMed, CrossRef
  26. Woo CW, Cui D, Arellano J, Dorweiler B, Harding H, Fitzgerald KA, Ron D, Tabas I. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat Cell Biol. 2009 Dec;11(12):1473-80. PubMed, CrossRef
  27. Kyriakakis E, Philippova M, Joshi MB, Pfaff D, Bochkov V, Afonyushkin T, Erne P, Resink TJ. T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis. Cell Signal. 2010 Sep;22(9):1308-16. PubMed, CrossRef
  28. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol. 2012 Jun 25;197(7):857-67. Review. PubMed, PubMedCentral, CrossRef
  29. Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ. The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Proc Natl Acad Sci USA. 2006 Sep 26;103(39):14343-8. PubMed, PubMedCentral, CrossRef
  30. 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-specific transcriptional regulatory networks. Mol Cell. 2007 Jul 6;27(1):53-66. PubMed, CrossRef
  31. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009 Aug 10;186(3):323-31. PubMed, PubMedCentral, CrossRef
  32. Han D, Upton JP, Hagen A, Callahan J, Oakes SA, Papa FR. A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress. Biochem Biophys Res Commun. 2008 Jan 25;365(4):777-83.  PubMed, CrossRef
  33. Bouchecareilh M, Higa A, Fribourg S, Moenner M, Chevet E. Peptides derived from the bifunctional kinase/RNase enzyme IRE1α modulate IRE1α activity and protect cells from endoplasmic reticulum stress. FASEB J. 2011 Sep;25(9):3115-29. PubMed, CrossRef
  34. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008 Sep;8(9):705-13. PubMed, CrossRef
  35. Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, Hawkins C, Guha A. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med. 2011 Feb 14;208(2):313-26.  PubMedPubMed, CrossRef
  36. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, Caro J. Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem. 2002 Feb 22;277(8):6183-7. PubMed, PubMedCentral, CrossRef
  37. Bartrons R, Caro J. Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr. 2007 Jun;39(3):223-9. Review. PubMed, CrossRef
  38. Minchenko O, Opentanova I, Minchenko D, Ogura T, Esumi H. Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett. 2004 Oct 8;576(1-2):14-20. PubMed, CrossRef
  39. Minchenko OH, Ochiai A, Opentanova IL, Ogura T, Minchenko DO, Caro J, Komisarenko SV, Esumi H. Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie. 2005 Nov;87(11):1005-10. PubMed, CrossRef
  40. Chesney J. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care. 2006 Sep;9(5):535-9. Review. PubMed, CrossRef
  41. Zou J, Li P, Lu F, Liu N, Dai J, Ye J, Qu X, Sun X, Ma D, Park J, Ji C. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells. J Hematol Oncol. 2013 Jan 5;6:3. PubMed, PubMedCentral, CrossRef
  42. Feldman DE, Chauhan V, Koong AC. The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res. 2005 Nov;3(11):597-605. Review. PubMed, CrossRef
  43. Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9. Review. PubMed
  44. Magagnin MG, Koritzinsky M, Wouters BG. Patterns of tumor oxygenation and their influence on the cellular hypoxic response and hypoxia-directed therapies. Drug Resist Updat. 2006 Aug-Oct;9(4-5):185-97. Review. PubMed
  45. Moenner M, Pluquet O, Bouchecareilh M, Chevet E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Res. 2007 Nov 15;67(22):10631-4. Review. PubMed
  46. Nagelkerke A, Bussink J, Mujcic H, Wouters BG, Lehmann S, Sweep FC, Span PN. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res. 2013 Jan 7;15(1):R2. PubMed, PubMedCentral, CrossRef
  47. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D, Diehl JA. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene. 2010 Jul 8;29(27):3881-95.  PubMed, PubMedCentral, CrossRef
  48. Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, Le QT, Koong AC. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 2004 Sep 1;64(17):5943-7. PubMed
  49. Koumenis C. ER stress, hypoxia tolerance and tumor progression. Curr Mol Med. 2006 Feb;6(1):55-69. Review. PubMed
  50. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005 Oct 5;24(19):3470-81. PubMed, PubMedCentral, CrossRef
  51. Mahadevan NR, Rodvold J, Sepulveda H, Rossi S, Drew AF, Zanetti M. Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells. Proc Natl Acad Sci USA. 2011 Apr 19;108(16):6561-6. PubMed, PubMedCentral, CrossRef
  52. Mahadevan NR, Zanetti M. Tumor stress inside out: cell-extrinsic effects of the unfolded protein response in tumor cells modulate the immunological landscape of the tumor microenvironment. J Immunol. 2011 Nov 1;187(9):4403-9. Review. PubMed, CrossRef
  53. Auf G, Jabouille A, Guérit S, Pineau R, Delugin M, Bouchecareilh M, Magnin N, Favereaux A, Maitre M, Gaiser T, von Deimling A, Czabanka M, Vajkoczy P, Chevet E, Bikfalvi A, Moenner M. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci USA. 2010 Aug 31;107(35):15553-8. PubMed, PubMedCentral, CrossRef
  54. Romero-Ramirez L, Cao H, Regalado MP, Kambham N, Siemann D, Kim JJ, Le QT, Koong AC. X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Transl Oncol. 2009 Mar;2(1):31-8. PubMed, PubMedCentral, CrossRef
  55. Thorpe JA, Schwarze SR. IRE1alpha controls cyclin A1 expression and promotes cell proliferation through XBP-1. Cell Stress Chaperones. 2010 Sep;15(5):497-508.  PubMed, PubMedCentral, CrossRef
  56. Cao SS, Kaufman RJ. Targeting endoplasmic reticulum stress in metabolic disease. Expert Opin Ther Targets. 2013 Apr;17(4):437-48. Review. PubMed, CrossRef
  57. Drogat B, Bouchecareilh M, North S, Petibois C, Déléris G, Chevet E, Bikfalvi A, Moenner M. Acute L-glutamine deprivation compromises VEGF-a upregulation in A549/8 human carcinoma cells. J Cell Physiol. 2007 Aug;212(2):463-72. PubMed, CrossRef
  58. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002 Nov;22(21):7405-16. PubMed, PubMedCentral, CrossRef
  59. Ozawa K, Kuwabara K, Tamatani M, Takatsuji K, Tsukamoto Y, Kaneda S, Yanagi H, Stern DM, Eguchi Y, Tsujimoto Y, Ogawa S, Tohyama M. 150-kDa oxygen-regulated protein (ORP150) suppresses hypoxia-induced apoptotic cell death. J Biol Chem. 1999 Mar 5;274(10):6397-404. PubMed, CrossRef
  60. Neelam S, Brooks MM, Cammarata PR. Lenticular cytoprotection. Part 1: the role of hypoxia inducible factors-1α and -2α and vascular endothelial growth factor in lens epithelial cell survival in hypoxia. Mol Vis. 2013;19:1-15. PubMed, PubMedCentral
  61. Mozos A, Roué G, López-Guillermo A, Jares P, Campo E, Colomer D, Martinez A. The expression of the endoplasmic reticulum stress sensor BiP/GRP78 predicts response to chemotherapy and determines the efficacy of proteasome inhibitors in diffuse large b-cell lymphoma. Am J Pathol. 2011 Nov;179(5):2601-10. PubMed, PubMedCentral, CrossRef
  62. Minchenko DO, Karbovskyi LL, Danilovskyi SV, Kharkova AP,  Minchenko OH. Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation. Nat Sci. 2012;4(1):38-46. CrossRef
  63.  Minchenko DO, Kharkova AP, Hubenia OV, Minchenko OH. Insulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation. Endocr Regul. 2013 Jan;47(1):15-26. PubMed, CrossRef
  64. 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. 2007 Jul 15;67(14):6700-7. PubMed, CrossRef
  65. Minchenko DO, Hubenya OV, Terletsky BM, Moenner M, Minchenko OH. Effect of glutamine or glucose deprivation on the expression of cyclin and cyclin-dependent kinase genes in glioma cell line U87 and its subline with suppressed activity of signaling enzyme of endoplasmic reticulum-nuclei-1. Ukr Biokhim Zhurn. 2011 Jan-Feb;83(1):18-29. PubMed
  66. Minchenko DО,  Kubajchuk KІ, Ratushna OO, Komisarenko SV, Minchenko OH. The effect of hypoxia and ischemic condition on the expression of vEGF genes in glioma U87 cells is dependent from ERN1 knockdown. Adv  Biol Chem. 2012;2(2):198-206. CrossRef
  67. Minchenko DO, Karbovskyi LL, Danilovskyi SV, Moenner M, Minchenko OH. Effect of hypoxia and glutamine or glucose deprivation on the expression of retinoblastoma and retinoblastoma-related genes in ERN1 knockdown glioma U87 cell line. Am J Mol Biol. 2012;2(1):21-31. CrossRef
  68.  Lee J, Sun C, Zhou Y, Lee J, Gokalp D, Herrema H, Park SW, Davis RJ, Ozcan U. p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med. 2011 Sep 4;17(10):1251-60. PubMed, PubMedCentral, CrossRef
  69. Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U. The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med. 2010 Apr;16(4):429-37.  PubMed, PubMedCentralCrossRef
  70. Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Lee J, Fisher SJ, White MF, Biddinger SB, Ozcan U. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med. 2011 Mar;17(3):356-65. PubMed, PubMedCentral, CrossRef
  71. Minchenko D, Hubenya O, Terletsky B. et al. Blockade of the endoplasmic reticulum stress sensor inositol requiring enzyme-1 changes the expression of cyclin and growth arrest-specific genes in glioma cells. Annales Universitatis Mariae Curie-Sklodowska.  2010;23(3):179-184.
  72. Minchenko DM, Karbovsky LL, Terletsky BM, Hubenya OV, Moenner M, Minchenko OH. Effect of hypoxia, glutamine and glucose deprivation  on the expression of cyclin B1, B2, C, G1, H, I, Т2 and some cyclin-dependent genes in glioma cells. Physics Alive. 2010;18(2):110-120.
  73. Minchenko DO, Karbovskyi LL, Danylovsky SV, Moenner M, Minchenko OH. Effect of hypoxia, glutamine and glucose deprivation on the expression of mRNA of the retinoblastoma binding proteins in glioma cells. Studia Biologica. 2011;5(1):57-68.
  74. Karbovskyi LL, Minchenko DO, Harmash YA, Minchenko OH. Molecula r mechanisms of circa dian clock functioning. Ukr Biokhim Zhurn. 2011 May-Jun;83(3):5-24. PubMed
  75. Karbovskyi LL, Minchenko DO, Danylovskyi SV, Moenner M, Minchenko OH. Endoplasmic reticulum–nuclei sugnaling enzyme-1 knockdown modulates effect of hypoxia and ischemia on the expression of circadian genes in glioma cells. Studia Biologica. 2011;5(2):37-50.
  76. Minchenko DO, Gubenya OV, Kharkova AP.  Nauk. Visnyk Bogomolets Nat. Med. Univ. 2011;(1(32)):26-34.
  77. Lypova NM, Minchenko DM, Kubaichuk KI, Minchenko ОH. Expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-1 and -2 and its unique alternative splice variants in U87 glioma cells with ERN1 loss of function. Physics Alive. 2011;19(1):40-51.
  78. Minchenko DO, Marunych RY, Khomenko EV, Bakalets TV, Minchenko OH. Expression of hexokinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphoaphatase gehes in ERN1 knockdown glioma U87 cells: effeect of hypoxia and glutamine or glucose deprivation. Studia Biologica. 2011;5(3):5-18.
  79. Kubaichuk KI, Minchenko DO, Danilovskyi SV, Kuznetsova AY, Jasim AK, Minchenko OH. Hypoxic regulation of the expression of anti-angiogenic genes in U87 Glioma cells with loss of function of ERN1 signaling enzyme. Studia Biologica. 2012;6(3):15-28.
  80. Kang FW, Gao Y, Que L, Sun J, Wang ZL. Hypoxia-inducible factor-1α overexpression indicates poor clinical outcomes in tongue squamous cell carcinoma. Exp Ther Med. 2013 Jan;5(1):112-118. PubMed, PubMedCentral, CrossRef
  81.  Agani F, Jiang BH. Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets. 2013 Mar;13(3):245-51. Review. PubMed, CrossRef
  82. Marunych RY, Minchenko DM, Kubaichuk KI, Bakalets TV, Minchenko ОH. Effect of hypoxia and ischemia on the expression of phosphofructokinase-1 and lactate dehydrogenase genes in glioma U87 cells with ERN1 knockdown.  Physics Alive. 2011;19(1):52-60.

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.