Skip to main content

Advertisement

SpringerLink
Log in

The Promoting Effect of Radiation on Glucose Metabolism in Breast Cancer Cells under the Treatment of Cobalt Chloride

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

We aimed to investigate the influence of radiation on hypoxia-treated breast cancers cells and its underlying mechanism. We mimicked the hypoxic response in MCF-7 cells by the treatment of CoCl2. Meanwhile, hypoxic MCF-7 cells induced by CoCl2 or untreated MCF-7 cells were treated with or without radiation, and then treated with or without hypoxia inducible factors-1α (HIF-1α) inhibitor. Subsequently, glucose update and lactate release rate were determined by commercial kits, as well as the expressions of HIF-1α and the glucose metabolic pathway related genes, including fructose biphoshatase 1 (FBP1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase 2 (HK2), and isocitrate dehydrogenase 2 (IDH20) were detected by western blotting and/or RT-PCR. The results showed that glucose uptake rate and lactate release rate were increased in cells under hypoxia and/or radiation condition compared with untreated cells (p < 0.05), while the addition of HIF-1α inhibitor decreased these rates in hypoxia + radiation treated cells (p < 0.05). In addition, compared with untreated cells, the mRNA and protein levels of HIF-1α were significantly increased under hypoxia and radiation condition (p < 0.05), while which decreased after the addition of HIF-1α inhibitor (p < 0.05). Similar content changing trends (all p < 0.05) were observed in FBP1, IDH2, GLUT1, and LDHA but not HK2. In conclusion, the combination of radiation and hypoxia could promote the glucose metabolism. Furthermore, HIF-1α might inhibit the promoting effect of radiation on glycolysis in hypoxic MCF-7 cells by regulating the glucose metabolic pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

FBP1:

Fructose biphoshatase 1

LDHA:

Lactate dehydrogenase A

HK2:

Hexokinase 2

IDH2:

Isocitrate dehydrogenase 2

GLUT1:

Glucose transporter 1

HIFs:

Hypoxia inducible factors

BCA:

Bicinchinoninic acid

References

  1. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics. CA Cancer J Clin 64(1):9–29

    Article  PubMed  Google Scholar 

  2. Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H (2014) Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer 21(6):703–714

    Article  PubMed  Google Scholar 

  3. Lundgren K, Nordenskjöld B, Landberg G (2009) Hypoxia, snail and incomplete epithelial–mesenchymal transition in breast cancer. Br J Cancer 101(10):1769–1781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354

    Article  CAS  PubMed  Google Scholar 

  5. Mees G, Dierckx R, Vangestel C, Van de Wiele C (2009) Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging 36(10):1674–1686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zeng W, Liu P, Pan W, Singh SR, Wei Y (2015) Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett 356(2):263–267

    Article  CAS  PubMed  Google Scholar 

  7. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899

    Article  CAS  PubMed  Google Scholar 

  8. Daşu A, Toma-Daşu I, Karlsson M (2003) Theoretical simulation of tumour oxygenation and results from acute and chronic hypoxia. Phys Med Biol 48(17):2829

    Article  PubMed  Google Scholar 

  9. Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R, Giaccia AJ (2003) Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22(37):5907–5914

    Article  CAS  PubMed  Google Scholar 

  10. Brahimi-Horn MC, Chiche J, Pouyssegur J (2007) Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19(2):223–229

    Article  CAS  PubMed  Google Scholar 

  11. J-w K, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185

    Article  Google Scholar 

  12. Semenza GL (2011) Oxygen sensing, homeostasis, and disease. New England J Med 365(6):537–547

    Article  CAS  Google Scholar 

  13. Germain S, Monnot C, Muller L, Eichmann A (2010) Hypoxia-driven angiogenesis: role of tip cells and extracellular matrix scaffolding. Curr Opin Hematol 17(3):245–251

    CAS  PubMed  Google Scholar 

  14. Baker L, Boult J, Walker-Samuel S, Chung Y, Jamin Y, Ashcroft M, Robinson S (2012) The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. Br J Cancer 106(10):1638–1647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cairns RA, Papandreou I, Sutphin PD, Denko NC (2007) Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci 104(22):9445–9450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu Y, Liu J, Huang H (2013) Recent agents targeting HIF-1α for cancer therapy. J Cell Biochem 114(3):498–509

    Article  CAS  PubMed  Google Scholar 

  17. Lu H, Li X, Luo Z, Liu J, Fan Z (2013) Cetuximab reverses the Warburg effect by inhibiting HIF-1–regulated LDH-A. Mol Cancer Ther 12(10):2187–2199

    Article  CAS  PubMed  Google Scholar 

  18. Lagadec C, Dekmezian C, Bauche L, Pajonk F (2012) Oxygen levels do not determine radiation survival of breast cancer stem cells. PLoS One 7(3):29

    Article  Google Scholar 

  19. Chandel N, Maltepe E, Goldwasser E, Mathieu C, Simon M, Schumacker P (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci 95(20):11715–11720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jiang B-H, Zheng JZ, Leung SW, Roe R, Semenza GL (1997) Transactivation and inhibitory domains of hypoxia-inducible factor 1α modulation of transcriptional activity by oxygen tension. J Biol Chem 272(31):19253–19260

    Article  CAS  PubMed  Google Scholar 

  21. An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM (1998) Stabilization of wild-type p53 by hypoxia-inducible factor 1α. Nature 392(6674):405–408

    Article  CAS  PubMed  Google Scholar 

  22. Wang G, Hazra TK, Mitra S, Lee H-M, Englander EW (2000) Mitochondrial DNA damage and a hypoxic response are induced by CoCl2 in rat neuronal PC12 cells. Nucleic Acids Symp Ser 28(10):2135–2140

    Article  CAS  Google Scholar 

  23. Lagadec C, Dekmezian C, Bauché L, Pajonk F (2012) Oxygen levels do not determine radiation survival of breast cancer stem cells. PLoS One 7(3):e34545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hoogsteen I, Marres H, Van Der Kogel A, Kaanders J (2007) The hypoxic tumour microenvironment, patient selection and hypoxia-modifying treatments. Clin Oncol 19(6):385–396

    Article  CAS  Google Scholar 

  25. Horsman MR, Wouters BG, Joiner MC, Overgaard J (2009) The oxygen effect and fractionated radiotherapy. Basic clinical radiobiology London: Edward Arnold: 207–209

  26. Gillies RJ, Gatenby RA (2007) Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr 39(3):251–257

    Article  CAS  PubMed  Google Scholar 

  27. Ganapathy V, Thangaraju M, Prasad PD (2009) Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther 121(1):29–40

    Article  CAS  PubMed  Google Scholar 

  28. Harrison L, Blackwell K (2004) Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? The Oncologist 9(Supplement 5):31–40

    Article  PubMed  Google Scholar 

  29. Sattler UG, Mueller-Klieser W (2009) The anti-oxidant capacity of tumour glycolysis. Int J Radiat Biol 85(11):963–971

    Article  CAS  PubMed  Google Scholar 

  30. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T (2013) Loss of FBP1 by snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23(3):316–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13(3):310–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Behrooz A, Ismail-Beigi F (1997) Dual control of glut1 glucose transporter gene expression by hypoxia and by inhibition of oxidative phosphorylation. J Biol Chem 272(9):5555–5562

    Article  CAS  PubMed  Google Scholar 

  33. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Aimee YY (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12(2):149–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ward PS, Thompson CB (2012) Signaling in control of cell growth and metabolism. Cold Spring Harb Perspect Biol 4(7):a006783

    Article  PubMed  PubMed Central  Google Scholar 

  35. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6):425–434

    Article  CAS  PubMed  Google Scholar 

  36. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ (2009) IDH1 and IDH2 mutations in gliomas. New England J Med 360(8):765–773

    Article  CAS  Google Scholar 

  37. Drabovich AP, Pavlou MP, Dimitromanolakis A, Diamandis EP (2012) Quantitative analysis of energy metabolic pathways in MCF-7 breast cancer cells by selected reaction monitoring assay. Mol Cell Proteomics 11(8):422–434

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lee J-W, Bae S-H, Jeong J-W, Kim S-H, Kim K-W (2004) Hypoxia-inducible factor (HIF-1) α: its protein stability and biological functions. Exp Mol Med 36(1):1–12

    Article  PubMed  Google Scholar 

  39. Wang B, Wood IS, Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 455(3):479–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ellinghaus P, Heisler I, Unterschemmann K, Haerter M, Beck H, Greschat S, Ehrmann A, Summer H, Flamme I, Oehme F (2013) BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med 2(5):611–624

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tennant DA, Durán RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10(4):267–277

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, the Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China

    Chun-bo Zhao

  2. Department of Radiation Oncology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

    Lei Shi

  3. Department of Internal Medicine, the Third Affiliated Hospital of Harbin Medical University, 150 Haping Road, Nangang District, Harbin, Heilongjiang Province, 150086, China

    Hai-hong Pu & Qing-yuan Zhang

Authors
  1. Chun-bo Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai-hong Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qing-yuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qing-yuan Zhang.

Ethics declarations

Competing Interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Cb., Shi, L., Pu, Hh. et al. The Promoting Effect of Radiation on Glucose Metabolism in Breast Cancer Cells under the Treatment of Cobalt Chloride. Pathol. Oncol. Res. 23, 47–53 (2017). https://doi.org/10.1007/s12253-016-0076-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-016-0076-3

Keywords

Search

Navigation