Journal of Bioenergetics and Biomembranes

, Volume 40, Issue 6, pp 607–618 | Cite as

Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells

ROS-mediated cell death by 3-BrPA
  • Ji Su Kim
  • Keun Jae Ahn
  • Jeong-Ah Kim
  • Hye Mi Kim
  • Jong Doo Lee
  • Jae Myun Lee
  • Se Jong Kim
  • Jeon Han Park
Article

Abstract

Hexokinase type II (HK II) is the key enzyme for maintaining increased glycolysis in cancer cells where it is overexpressed. 3-bromopyruvate (3-BrPA), an inhibitor of HK II, induces cell death in cancer cells. To elucidate the molecular mechanism of 3-BrPA-induced cell death, we used the hepatoma cell lines SNU449 (low expression of HKII) and Hep3B (high expression of HKII). 3-BrPA induced ATP depletion-dependent necrosis and apoptosis in both cell lines. 3-BrPA increased intracellular reactive oxygen species (ROS) leading to mitochondrial dysregulation. NAC (N-acetyl-l-cysteine), an antioxidant, blocked 3-BrPA-induced ROS production, loss of mitochondrial membrane potential and cell death. 3-BrPA-mediated oxidative stress not only activated poly-ADP-ribose (PAR) but also translocated AIF from the mitochondria to the nucleus. Taken together, 3-BrPA induced ATP depletion-dependent necrosis and apoptosis and mitochondrial dysregulation due to ROS production are involved in 3-BrPA-induced cell death in hepatoma cells.

Keywords

3-bromopyruvate ATP depletion-dependent necrosis Apoptosis ROS Mitochondrial dysregulation 

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References

  1. Adrain C, Creagh EM, Martin SJ (2001) Embo J 20:6627–6636CrossRefGoogle Scholar
  2. Blackburn RV, Spitz DR, Liu X, Galoforo SS, Sim JE, Ridnour LA, Chen JC, Davis BH, Corry PM, Lee YJ (1999) Free Radic Biol Med 26:419–430CrossRefGoogle Scholar
  3. Chang JM, Chung JW, Jae HJ, Eh H, Son KR, Lee KC, Park JH (2007) Acad Radiol 14:85–92CrossRefGoogle Scholar
  4. da-Silva WS, Gomez-Puyou A, de Gomez-Puyou MT, Moreno-Sanchez R, De Felice FG, de Meis L, Oliveira MF, Galina A (2004) J Biol Chem 279:39846–39855CrossRefGoogle Scholar
  5. Foubister V (2002) Drug Discov Today 7:934–935CrossRefGoogle Scholar
  6. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Cancer Res 62:3909–3913Google Scholar
  7. Geschwind JF, Georgiades CS, Ko YH, Pedersen PL (2004) Expert Rev Anticancer Ther 4:449–457CrossRefGoogle Scholar
  8. Gwak GY, Yoon JH, Kim KM, Lee HS, Chung JW, Gores GJ (2005) J Hepatol 42:358–364CrossRefGoogle Scholar
  9. Higuchi Y (2004) J Cell Mol Med 8:455–464CrossRefGoogle Scholar
  10. Kakkar P, Singh BK (2007) Mol Cell Biochem 305:235–253CrossRefGoogle Scholar
  11. Kang YH, Yi MJ, Kim MJ, Park MT, Bae S, Kang CM, Cho CK, Park IC, Park MJ, Rhee CH, Hong SI, Chung HY, Lee YS, Lee SJ (2004) Cancer Res 64:8960–8967CrossRefGoogle Scholar
  12. Kim JS, Lee JM, Chwae YJ, Kim YH, Lee JH, Kim K, Lee TH, Kim SJ, Park JH (2004) Biochem Pharmacol 67:1459–1468CrossRefGoogle Scholar
  13. Kim W, Yoon JH, Jeong JM, Cheon GJ, Lee TS, Yang JI, Park SC, Lee HS (2007) Mol Cancer Ther 6:2554–2562CrossRefGoogle Scholar
  14. Ko YH, Pedersen PL, Geschwind JF (2001) Cancer Lett 173:83–91CrossRefGoogle Scholar
  15. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Biochem Biophys Res Commun 324:269–275CrossRefGoogle Scholar
  16. Korshunov SS, Skulachev VP, Starkov AA (1997) FEBS Lett 416:15–18CrossRefGoogle Scholar
  17. Kroemer G, Reed JC (2000) Nat Med 6:513–519CrossRefGoogle Scholar
  18. Lemasters JJ (2005) Gastroenterology 129:351–360CrossRefGoogle Scholar
  19. Li GY, Osborne NN (2008) Brain Res 1188:35–43CrossRefGoogle Scholar
  20. Mathupala SP, Rempel A, Pedersen PL (1995) J Biol Chem 270:16918–16925CrossRefGoogle Scholar
  21. Mathupala SP, Ko YH, Pedersen PL (2006) Oncogene 25:4777–4786CrossRefGoogle Scholar
  22. McEligot AJ, Yang S, Meyskens FL Jr (2005) Annu Rev Nutr 25:261–295CrossRefGoogle Scholar
  23. Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K (2005) Embo J 24:1375–1386CrossRefGoogle Scholar
  24. Park JG, Lee JH, Kang MS, Park KJ, Jeon YM, Lee HJ, Kwon HS, Park HS, Yeo KS, Lee KU et al (1995) Int J Cancer 62:276–282CrossRefGoogle Scholar
  25. Pastorino JG, Hoek JB, Shulga N (2005) Cancer Res 65:10545–10554CrossRefGoogle Scholar
  26. Prasad V, Chandele A, Jagtap JC, Sudheer Kumar P, Shastry P (2006) Free Radic Biol Med 41:431–442CrossRefGoogle Scholar
  27. Spitz DR, Sim JE, Ridnour LA, Galoforo SS, Lee YJ (2000) Ann N Y Acad Sci 899:349–362CrossRefGoogle Scholar
  28. Ueda S, Masutani H, Nakamura H, Tanaka T, Ueno M, Yodoi J (2002) Antioxid Redox Signal 4:405–414CrossRefGoogle Scholar
  29. Vali M, Liapi E, Kowalski J, Hong K, Khwaja A, Torbenson MS, Georgiades C, Geschwind JF (2007) J Vasc Interv Radiol 18:95–101CrossRefGoogle Scholar
  30. van Wijk SJ, Hageman GJ (2005) Free Radic Biol Med 39:81–90Google Scholar
  31. Vincent AM, McLean LL, Backus C, Feldman EL (2005) FASEB J 19:638–640Google Scholar
  32. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P (2005) Cancer Res 65:613–621CrossRefGoogle Scholar
  33. Xu Y, Huang S, Liu ZG, Han J (2006) J Biol Chem 281:8788–8795CrossRefGoogle Scholar
  34. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2002) Science 297:259–263CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ji Su Kim
    • 1
    • 5
  • Keun Jae Ahn
    • 2
  • Jeong-Ah Kim
    • 3
    • 6
  • Hye Mi Kim
    • 4
  • Jong Doo Lee
    • 2
  • Jae Myun Lee
    • 1
  • Se Jong Kim
    • 1
  • Jeon Han Park
    • 1
  1. 1.Department of Microbiology and Brain Korea 21 Project for Medical Sciences, Institute for Immunology and Immunological DiseasesYonsei University College of MedicineSeoulSouth Korea
  2. 2.Division of Nuclear Medicine, Department of Diagnostic RadiologyYonsei University College of MedicineSeoulSouth Korea
  3. 3.Department of Radiology, Cheil General Hospital and Women’s Healthcare CenterKwandong University College of MedicineSeoulSouth Korea
  4. 4.Department of Diagnostic RadiologyYonsei University College of MedicineSeoulSouth Korea
  5. 5.Yonsei Cancer Research InstituteYonsei University College of MedicineSeoulSouth Korea
  6. 6.Department of Radiology, Yongdong Severance HospitalYonsei University College of MedicineSeoulSouth Korea

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