Login Register Cart 0
Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Continuous Hypoxia and Glucose Metabolism: The Effects on Gene Expression in Mcf7 Breast Cancer Cell Line

Author(s): Abdel Q. Al Bawab, Malek Zihlif*, Yazan Jarrar and Ahmad Sharab

Volume 21, Issue 3, 2021

Published on: 06 May, 2020

Page: [511 - 519] Pages: 9

DOI: 10.2174/1871530320666200506082020

Price: $65

Abstract

Background: Hypoxia (deprived oxygen in tissues) may induce molecular and genetic changes in cancer cells.

Objective: To Investigate the genetic changes of glucose metabolism in breast cancer cell line (MCF7) after exposure to continuous hypoxia (10 and 20 cycles exposure of 72 hours continuously on a weekly basis).

Methods: Gene expression of MCF7 cells was evaluated using real-time polymerase chain reactionarray method. Furthermore, cell migration and wound healing assays were also applied.

Results: It was found that 10 episodes of continuous hypoxia activated the Warburg effect in MCF7 cells, via the significant up-regulation of genes involved in glycolysis (ANOVA, p value < 0.05). The molecular changes were associated with the ability of MCF7 cells to divide and migrate. Interestingly, after 20 episodes of continuous hypoxia, the expression glycolysis mediated genes dropped significantly (from 30 to 9 folds). This could be attributed to the adaptive ability of cancer cells.

Conclusion: It is concluded that 10 hypoxic episodes increased the survival rate and aggressiveness of MCF7 cells and induced the Warburg effect by the up-regulation of the glycolysis mediating gene expression.

Keywords: Hypoxia, chronic, MCF7, glycolysis, RT-PCR, warburg effect.

« Previous Next »
Graphical Abstract

[1]
Giordano, F.J. Oxygen, oxidative stress, hypoxia, and heart failure. J. Clin. Invest., 2005, 115(3), 500-508.
[http://dx.doi.org/10.1172/JCI200524408] [PMID: 15765131]
[2]
Marie-Egyptienne, D.T.; Lohse, I.; Hill, R.P. Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Lett., 2013, 341(1), 63-72.
[http://dx.doi.org/10.1016/j.canlet.2012.11.019] [PMID: 23200673]
[3]
Eales, K.L.; Hollinshead, K.E.R.; Tennant, D.A. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis, 2016, 5(1)e190
[http://dx.doi.org/10.1038/oncsis.2015.50] [PMID: 26807645]
[4]
Heddleston, J.M.; Li, Z.; Lathia, J.D.; Bao, S.; Hjelmeland, A.B.; Rich, J.N. Hypoxia inducible factors in cancer stem cells. Br. J. Cancer, 2010, 102(5), 789-795.
[http://dx.doi.org/10.1038/sj.bjc.6605551] [PMID: 20104230]
[5]
Cairns, R.A.; Harris, I.S.; Mak, T.W. Regulation of cancer cell metabolism. Nat. Rev. Cancer, 2011, 11(2), 85-95.
[http://dx.doi.org/10.1038/nrc2981] [PMID: 21258394]
[6]
Bailey-Serres, J.; Fukao, T.; Gibbs, D.J.; Holdsworth, M.J.; Lee, S.C.; Licausi, F.; Perata, P.; Voesenek, L.A.C.J.; van Dongen, J.T. Making sense of low oxygen sensing. Trends Plant Sci., 2012, 17(3), 129-138.
[http://dx.doi.org/10.1016/j.tplants.2011.12.004] [PMID: 22280796]
[7]
Krock, B.L.; Skuli, N.; Simon, M.C. Hypoxia-induced angiogenesis: good and evil. Genes Cancer, 2011, 2(12), 1117-1133.
[http://dx.doi.org/10.1177/1947601911423654] [PMID: 22866203]
[8]
Hung, S-P.; Ho, J.H.; Shih, Y-R.V.; Lo, T.; Lee, O.K. Hypoxia promotes proliferation and osteogenic differentiation potentials of human mesenchymal stem cells. J. Orthop. Res., 2012, 30(2), 260-266.
[http://dx.doi.org/10.1002/jor.21517] [PMID: 21809383]
[9]
Semenza, G.L. Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb. Symp. Quant. Biol., 2011, 76, 347-353.
[http://dx.doi.org/10.1101/sqb.2011.76.010678] [PMID: 21785006]
[10]
Scanlon, S.E.; Glazer, P.M. Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment. DNA Repair (Amst.), 2015, 32, 180-189.
[http://dx.doi.org/10.1016/j.dnarep.2015.04.030] [PMID: 25956861]
[11]
Al Tameemi, W.; Dale, T.P.; Al-Jumaily, R.M.K.; Forsyth, N.R. Hypoxia-modified cancer cell metabolism. Front. Cell Dev. Biol., 2019, 7, 4.
[http://dx.doi.org/10.3389/fcell.2019.00004] [PMID: 30761299]
[12]
Ganapathy-Kanniappan, S.; Geschwind, J-F.H. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol. Cancer, 2013, 12(1), 152.
[http://dx.doi.org/10.1186/1476-4598-12-152] [PMID: 24298908]
[13]
Liu, Y.; Song, X.; Wang, X.; Wei, L.; Liu, X.; Yuan, S.; Lv, L. Effect of chronic intermittent hypoxia on biological behavior and hypoxia-associated gene expression in lung cancer cells. J. Cell. Biochem., 2010, 111(3), 554-563.
[http://dx.doi.org/10.1002/jcb.22739] [PMID: 20568121]
[14]
Sun, G.; Zhou, Y.; Li, H.; Guo, Y.; Shan, J.; Xia, M.; Li, Y.; Li, S.; Long, D.; Feng, L. Over-expression of microRNA-494 upregulates hypoxia-inducible factor-1 alpha expression via PI3K/Akt pathway and protects against hypoxia-induced apoptosis. J. Biomed. Sci., 2013, 20(1), 100.
[http://dx.doi.org/10.1186/1423-0127-20-100] [PMID: 24364919]
[15]
Fodale, V.; Pierobon, M.; Liotta, L.; Petricoin, E. Mechanism of cell adaptation: when and how do cancer cells develop chemoresistance? Cancer J., 2011, 17(2), 89-95.
[http://dx.doi.org/10.1097/PPO.0b013e318212dd3d] [PMID: 21427552]
[16]
Joseph, J.P.; Harishankar, M.K.; Pillai, A.A.; Devi, A. Hypoxia induced EMT: a review on the mechanism of tumor progression and metastasis in OSCC. Oral Oncol., 2018, 80, 23-32.
[http://dx.doi.org/10.1016/j.oraloncology.2018.03.004] [PMID: 29706185]
[17]
Carnero, A.; Lleonart, M. The hypoxic microenvironment: a determinant of cancer stem cell evolution. BioEssays, 2016, 38(Suppl. 1), S65-S74.
[http://dx.doi.org/10.1002/bies.201670911] [PMID: 27417124]
[18]
McKeown, S.R. Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br. J. Radiol., 2014, 87(1035)20130676
[http://dx.doi.org/10.1259/bjr.20130676] [PMID: 24588669]
[19]
Leithner, K.; Wohlkoenig, C.; Stacher, E.; Lindenmann, J.; Hofmann, N.A.; Gallé, B.; Guelly, C.; Quehenberger, F.; Stiegler, P.; Smolle-Jüttner, F-M.; Philipsen, S.; Popper, H.H.; Hrzenjak, A.; Olschewski, A.; Olschewski, H. Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model - role of tumor stroma cells. BMC Cancer, 2014, 14, 40.
[http://dx.doi.org/10.1186/1471-2407-14-40] [PMID: 24460801]
[20]
Challapalli, A.; Carroll, L.; Aboagye, E.O. Molecular mechanisms of hypoxia in cancer. Clin. Transl. Imaging, 2017, 5(3), 225-253.
[http://dx.doi.org/10.1007/s40336-017-0231-1] [PMID: 28596947]
[21]
Vaupel, P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologis, 2008, 13(Suppl. 3), 21-26.
[http://dx.doi.org/10.1634/theoncologist.13-S3-21]] [PMID: 18458121]
[22]
Xia, Y.; Jiang, L.; Zhong, T. The role of HIF-1α in chemo-/radioresistant tumors. OncoTargets Ther., 2018, 11, 3003-3011.
[http://dx.doi.org/10.2147/OTT.S158206] [PMID: 29872312]
[23]
Hielscher, A.; Gerecht, S. Hypoxia and free radicals: role in tumor progression and the use of engineering-based platforms to address these relationships. Free Radic. Biol. Med., 2015, 79, 281-291.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.09.015] [PMID: 25257256]
[24]
Milani, M.; Harris, A.L. Targeting tumour hypoxia in breast cancer. Eur. J. Cancer, 2008, 44(18), 2766-2773.
[http://dx.doi.org/10.1016/j.ejca.2008.09.025] [PMID: 18990559]
[25]
Gee, M.S.; Makonnen, S.; al-Kofahi, K.; Roysam, B.; Payvandi, F.; Man, H-W.; Muller, G.W.; Lee, W.M.F. Hypoxia-mediated apoptosis from angiogenesis inhibition underlies tumor control by recombinant interleukin 12. Cancer Res., 2003, 59(19), 4882-4889.
[PMID: 10519400]
[26]
Zhu, Q.; Shan, C.; Li, L.; Song, L.; Zhang, K.; Zhou, Y. Differential expression of genes associated with hypoxia pathway on bone marrow stem cells in osteoporosis patients with different bone mass index. Ann. Transl. Med., 2019, 7(14), 309.
[http://dx.doi.org/10.21037/atm.2019.06.27] [PMID: 31475179]
[27]
Rademakers, S.E.; Lok, J.; van der Kogel, A.J.; Bussink, J.; Kaanders, J.H.A.M. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer, 2011, 11, 167.
[http://dx.doi.org/10.1186/1471-2407-11-167] [PMID: 21569415]
[28]
Lum, J.J.; Bui, T.; Gruber, M.; Gordan, J.D.; DeBerardinis, R.J.; Covello, K.L.; Simon, M.C.; Thompson, C.B. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev., 2007, 21(9), 1037-1049.
[http://dx.doi.org/10.1101/gad.1529107] [PMID: 17437992]
[29]
Li, X-B.; Gu, J-D.; Zhou, Q-H. Review of aerobic glycolysis and its key enzymes - new targets for lung cancer therapy. Thorac. Cancer, 2015, 6(1), 17-24.
[http://dx.doi.org/10.1111/1759-7714.12148] [PMID: 26273330]
[30]
Zhang, J.Z.; Behrooz, A.; Ismail-Beigi, F. Regulation of glucose transport by hypoxia. Am. J. Kidney Dis., 1999, 34(1), 189-202.
[http://dx.doi.org/10.1016/S0272-6386(99)70131-9] [PMID: 10401038]
[31]
Helczynska, K.; Kronblad, A.; Jögi, A.; Nilsson, E.; Beckman, S.; Landberg, G.; Påhlman, S. Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res., 2003, 63(7), 1441-1444.
[PMID: 12670886]
[32]
Postovit, L-M.; Abbott, D.E.; Payne, S.L.; Wheaton, W.W.; Margaryan, N.V.; Sullivan, R.; Jansen, M.K.; Csiszar, K.; Hendrix, M.J.C.; Kirschmann, D.A. Hypoxia/reoxygenation: a dynamic regulator of lysyl oxidase-facilitated breast cancer migration. J. Cell. Biochem., 2008, 103(5), 1369-1378.
[http://dx.doi.org/10.1002/jcb.21517] [PMID: 17685448]
[33]
Muz, B.; de la Puente, P.; Azab, F.; Azab, A.K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl.), 2015, 3, 83-92.
[http://dx.doi.org/10.2147/HP.S93413] [PMID: 27774485]
[34]
Altenberg, B.; Greulich, K.O. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics, 2004, 84(6), 1014-1020.
[http://dx.doi.org/10.1016/j.ygeno.2004.08.010] [PMID: 15533718]
[35]
Kaelin, W.G., Jr; Thompson, C.B. Clues from cell metabolism. Nature, 2010, 465(7298), 562-564.
[http://dx.doi.org/10.1038/465562a] [PMID: 20520704]
[36]
Gray, L.R.; Tompkins, S.C.; Taylor, E.B. Regulation of pyruvate metabolism and human disease. Cell. Mol. Life Sci., 2014, 71(14), 2577-2604.
[http://dx.doi.org/10.1007/s00018-013-1539-2] [PMID: 24363178]
[37]
Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009, 324(5930), 1029-1033.
[http://dx.doi.org/10.1126/science.1160809] [PMID: 19460998]
[38]
Ricketts, C.J.; Shuch, B.; Vocke, C.D.; Metwalli, A.R.; Bratslavsky, G.; Middelton, L.; Yang, Y.; Wei, M-H.; Pautler, S.E.; Peterson, J.; Stolle, C.A.; Zbar, B.; Merino, M.J.; Schmidt, L.S.; Pinto, P.A.; Srinivasan, R.; Pacak, K.; Linehan, W.M. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J. Urol., 2012, 188(6), 2063-2071.
[http://dx.doi.org/10.1016/j.juro.2012.08.030] [PMID: 23083876]
[39]
Burns, J.S.; Manda, G. Metabolic pathways of the Warburg effect in health and disease: perspectives of choice, chain or chance. Int. J. Mol. Sci., 2017, 18(12)E2755
[http://dx.doi.org/10.3390/ijms18122755] [PMID: 29257069]
[40]
Gu, C.; Jun, J.C. Does hypoxia decrease the metabolic rate? Front. Endocrinol. (Lausanne), 2018, 9, 668.
[http://dx.doi.org/10.3389/fendo.2018.00668] [PMID: 30555410]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy