Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2016; 62(1): 3-15


Expression of proliferation related transcription factor genes in U87 glioma cells with IRE1 knockdown: upon glucose and glutamine deprivation

D.O. Tsymbal1, D.O. Minchenko1,2, I.V. Kryvdiuk1, O.O. Riabovol1, O.V. Halkin1, O.O. Ratushna1, O.H. Minchenko1

  1. Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine
  2. O.O. Bogomolets National Medical University, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz62.01.003


Abstract

Glycolysis and glutaminolysis as well as endoplasmic reticulum stress are required for tumor progression suggests through regulation of the cell cycle. Inhibition of ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme 1), a central mediator of endoplasmic reticulum stress, significantly suppresses glioma cell proliferation and tumor growth as well as modifies sensitivity gene expressions to glucose and glutamine deprivation. We have studied the expression of genes encoded transcription factors such as E2F8 (E2F transcription factor 8), EPAS1 (endothelial PAS domain protein 1), HOXC6 (homeobox C6), TBX3 (T-box 3), TBX2 (T-box 2), GTF2F2 (general transcription factor IIF), GTF2B (general transcription factor IIB), MAZ (MYC-associated zinc finger protein, purine-binding transcription factor), SNAI2 (snail family zinc finger 2), TCF3 (transcription factor 3), and TCF8/ZEB1 (zinc finger E-box binding homeobox 1)in U87 glioma cells upon glucose and glutamine deprivation in relation to inhibition of IRE1.We demonstrated that glutamine deprivation leads to up-regulation of the expression of EPAS1, TBX3, GTF2B, and MAZ genes and down-regulation of E2F8, GTF2F2, TCF8, and TBX2 genes in control glioma cells.At the same time, glucose deprivation enhances the expression of EPAS1 and GTF2B genes and decreases of E2F8, HOXC6, TCF3, and TBX2 genes in these glioma cells. Inhibition of IRE1 by dnIRE1 significantly modifies the expression most of studied genes with different magnitude. Present study demonstrates that fine-tuning of the expression of proliferation related transcription factor genes depends upon glucose and glutamine deprivation in IRE1-dependent manner and possibly contributes to slower tumor growth after inhibition of IRE1.

Keywords: mRNA expression;transcription factors; endoplasmic reticulum stress;IRE1 inhibition; glucose deprivation; glutamine deprivation;glioma cells

References

  1. Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell. 2014; 25(5): 563-73. CrossRef PubMed
  2.  
  3. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol. 2012; 197: 857-67. CrossRef PubMed PubMedCentral
  4.  
  5. Yadav RK, Chae SW, Kim HR, Chae HJ. Endoplasmic reticulum stress and cancer. J Cancer Prev. 2014; 19(2): 75-88. CrossRef PubMed PubMedCentral
  6.  
  7. Cao SS, Kaufman RJ. Targeting endoplasmic reticulum stress in metabolic disease. Expert OpinTher Targets. 2013; 17(4): 437-48. CrossRef PubMed
  8.  
  9. Bravo R1, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, Wang ZV, Zorzano A, Hill JA, Jaimovich E, Quest AF, Lavandero S. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 2013; 301: 215-90. CrossRef PubMed PubMedCentral
  10.  
  11. Manié 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. 2014; 307(10): C901-7. CrossRef PubMed
  12.  
  13. Minchenko OH, Kharkova AP, Bakalets TV, Kryvdiuk IV. Endoplasmic reticulum stress, its sensor and signaling systems and the role in the regulation of gene expressions in malignant tumor growth and hypoxia. Ukr Biochem J. 2013; 85(5): 5–16. CrossRef  
  14. Moenner M, Pluquet O, Bouchecareilh M, Chevet E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Res. 2007; 67(22):10631–4. CrossRef PubMed
  15.  
  16. 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 ischemiainduced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. CancerRes. 2007; 67(14): 6700–7. CrossRef PubMed
  17.  
  18. Auf G, Jabouille A, Guerit S,Pineau R, North S, Platonova N, Maitre M, Favereaux A, Vajkoczy P, Seno M, Bikfalvi A, Minchenko D, Minchenko O, Moenner M. Inositolrequiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci USA. 2010; 107(35): 15553–8. CrossRef PubMed PubMedCentral
  19.  
  20. Minchenko OH, Kubaichuk KI, Minchenko DO, Kovalevska OV, Kulinich AO, Lypova NM. Molecular mechanisms of IRE-1-mediated angiogenesis. Int J Physiol Pathophysiol. 2014; 5(1): 1-22. CrossRef  
  21. Colombo SL, Palacios-Callender M, Frakich N, Carcamo S, Kovacs I, Tudzarova S, Moncada S. Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. Proc Natl Acad Sci USA. 2011; 108(52): 21069-74. CrossRef PubMed PubMedCentral
  22.  
  23. Yalcin A, Clem BF, Imbert-Fernandez Y, Ozcan SC, Peker S, O'Neal J, Klarer AC, Clem AL, Telang S, Chesney J. 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death and Disease 2014; 5: e1337. CrossRef PubMed PubMedCentral
  24.  
  25. Huber AL, Lebeau J, Guillaumot P, Pétrilli V, Malek M, Chilloux J, Fauvet F, Payen L, Kfoury A, Renno T, Chevet E, Manié SN. p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Mol Cell. 2013; 49(6): 1049-59. CrossRef PubMed
  26.  
  27. Lenihan CR, Taylor CT. The impact of hypoxia on cell death pathways. Biochem Soc Trans. 2013; 41: 657–63. CrossRef PubMed
  28.  
  29. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013; 15(5): 481-90. CrossRef PubMed PubMedCentral
  30.  
  31. Maurel M, Chevet E, Tavernier J, Gerlo S. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci. 2014; 39(5): 245-54. CrossRef PubMed
  32.  
  33. Malhotra JD, Kaufman RJ. ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb Perspect Biol. 2011; 3: a004424. CrossRef PubMed PubMedCentral
  34.  
  35. Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer.Ann Med. 2014;46(4):233-43. CrossRef PubMed
  36.  
  37. Minchenko DO, Kubaichuk KI, Hubenia OV, Kryvdiuk IV, Kharkova AP, Herasymenko RM, Sulik RV, Karbovskyi LL, Minchenko OH. Endoplasmic reticulum stress and angiogenesis in cancer. Int J Physiol Pathophysiol. 2014; 5(3): 261-81. CrossRef  
  38. 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. High epiregulin expression in human U87 glioma cells relies on IRE1alpha and promotes autocrine growth through EGF receptor. BMC Cancer. 2013; 13: 597. CrossRef PubMed PubMedCentral
  39.  
  40. 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. 2013; 73(15): 4732–43. CrossRef PubMed PubMedCentral
  41.  
  42. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht DD. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Molecular Cell. 2007; 27: 53–66. CrossRef PubMed
  43.  
  44. 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; 186(3):323–31. CrossRef PubMed PubMedCentral
  45.  
  46. 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; 457(7230): 736–40. CrossRef PubMed PubMedCentral
  47.  
  48. Deng Q, Wang Q, Zong WY, Zheng DL, Wen YX, Wang KS, Teng XM, Zhang X, Huang J, Han ZG. E2F8 contributes to human hepatocellular carcinoma via regulating cell proliferation. Cancer Res. 2010; 70: 782-91. CrossRef PubMed
  49.  
  50. Christensen J, Cloos P, Toftegaard U, Klinkenberg D, Bracken AP, Trinh E, Heeran M, Di Stefano L, Helin K. Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription. Nucleic Acids Res. 2005; 33 (17): 5458-70. CrossRef PubMed PubMedCentral
  51.  
  52. Weijts BG, Bakker WJ, Cornelissen PW, Liang KH, Schaftenaar FH, Westendorp B, de Wolf CA, Paciejewska M, Scheele CL, Kent L, Leone G, Schulte-Merker S, deBruin A. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J. 2012; 31(19): 3871-84. CrossRef PubMed PubMedCentral
  53.  
  54. Washkowitz AJ, Gavrilov S, Begum S, Papaioannou VE. Diverse functional networks of Tbx3 in development and disease. Wiley Interdiscip Rev Syst Biol Med. 2012; 4: 273-83. CrossRef PubMed PubMedCentral
  55.  
  56. Li J, Weinberg MS, Zerbini L, Prince S. The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway. Mol Biol Cell. 2013; 24(22): 3569-76. CrossRef PubMed PubMedCentral
  57.  
  58. Zhang Q, Jin XS, Yang ZY, Wei M, Liu BY, Gu QL. Upregulated Hoxc6 expression is associated with poor survival in gastric cancer patients. Neoplasma. 2013; 60(4): 439-445. CrossRef PubMed
  59.  
  60. Raspaglio G, Petrillo M, Martinelli E, Li Puma DD, Mariani M, De Donato M, Filippetti F, Mozzetti S, Prislei S, Zannoni GF, Scambia G, Ferlini C. Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness. Gene. 2014; 542: 173-81. CrossRef PubMed
  61.  
  62. Bangoura G, Yang LY, Huang GW, Wang W. Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World J Gastroenterol. 2004; 10: 525-30. CrossRef PubMed PubMedCentral
  63.  
  64. Li L, Zhang A, Cao X, Chen J, Xia Y, Zhao H, Shen A. General transcription factor IIb overexpression and a potential link to proliferation in human hepatocellular carcinoma. Pathol Oncol Res. 2013; 19 (2): 195-203. CrossRef PubMed
  65.  
  66. Jiao L, Li Y, Shen D, Xu C, Wang L, Huang G, Chen L, Yang Y, Yang C, Yu Y, Sun Y. The prostate cancer-upregulated Myc-associated zinc-finger protein (MAZ) modulates proliferation and metastasis through reciprocal regulation of androgen receptor. Med Oncol. 2013; 30 (2): 570. CrossRef PubMed
  67.  
  68. Qian J, Liu H, Chen W, Wen K, Lu W, Huang C, Fu Z. Knockdown of Slug by RNAi inhibits the proliferation and invasion. of HCT116 colorectal cancer cells. Mol Med Rep. 2013; 8(4): 1055-9. PubMed
  69.  
  70. Wang Y, Wen M, Kwon Y, Xu Y, Liu Y, Zhang P, He X, Wang Q, Huang Y, Jen KY, LaBarge MA, You L, Kogan SC, Gray JW, Mao JH, Wei G. CUL4A induces epithelialmesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. Cancer Res. 2014; 74 (2): 520-31. CrossRef PubMed PubMedCentral
  71.  
  72. 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  
  73. Minchenko DO, Danilovskyi SV, Kryvdiuk IV, Bakalets TV, Yavorskyi VV, Sulik RV, Hubenia OV, Minchenko OH. Effect of glutamine and glucose deprivation on the expression of TP53, MDM2, USP7 and PERP genes in glioma U87 cells with IRE-1 knockdown. Int J Adv Med Sci. 2014; 2(2): 13-8.
  74.  
  75. Minchenko DO, Danilovskyi SV, Kryvdiuk IV, Hlushchak NA, Kovalevska OV, Karbovskyi LL, Minchenko OH. Acute L-glutamine deprivation affects the expression of TP53-related protein genes in U87 glioma cells. Fiziol Zh. 2014; 60(4): 11-21.  CrossRef PubMed
  76.  

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.