Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

Oncogene volume 27, pages 831–838 (2008)Cite this article

Abstract

Docetaxel is one of the most effective chemotherapeutic agents against cancer; nevertheless, some patients develop resistance. Unfortunately, their causes and mechanisms remain unknown. We created docetaxel-resistant DRHEp2 from human laryngeal cancer HEp2 and investigated the roles of mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) on docetaxel resistance. DRHEp2 had greatly increased mtDNA content. Reduction of mtDNA content in DRHEp2 by ethidium bromide treatment reduced the resistance. These results indicate the possible roles of mtDNA-coded enzymes in mitochondrial respiratory chain (MRC) in resistant mechanisms. Oligomycin A, an Fo-ATPase inhibitor, eliminated docetaxel resistance in DRHEp2; in contrast, inhibitors of other MRC did not. RNA interference targeted to Fo-ATPase d-subunit restored docetaxel-induced cytotoxicity to DRHEp2. These results indicate the roles of Fo-ATPase for resistant mechanisms. Docetaxel induced ROS generation in HEp2 but not in DRHEp2 and antioxidant pyrrolidine dithiocarbamate eliminated docetaxel-induced cytotoxicity, suggesting roles of ROS in docetaxel-induced cell death. Furthermore, inhibition of Fo-ATPase by Oligomycin A induced docetaxel-mediated ROS generation in DRHEp2. Taken together, DRHEp2 acquired docetaxel resistance through increasing Fo-ATPase, which led to diminish docetaxel-induced ROS generation and subsequently inhibited cell death. In conclusion, mtDNA plays an important role in developing docetaxel resistance through the reduction of ROS generation by regulating Fo-ATPase.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Adam D, Wiegmann K, Adam-Klages S, Ruff A, Kronke M . (1996). A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway. J Biol Chem 271: 14617–14622.

    Article  CAS  PubMed  Google Scholar 

  • Alexandre J, Batteux F, Nicco C, Chereau C, Laurent A, Guillevin L et al. (2006). Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer 119: 41–48.

    Article  CAS  PubMed  Google Scholar 

  • Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J et al. (1981). Sequence and organization of the human mitochondrial genome. Nature 290: 457–465.

    Article  CAS  PubMed  Google Scholar 

  • Bissery MC, Nohynek G, Sanderink GJ, Lavelle F . (1995). Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: preclinical experience. Anticancer Drugs 6: 339–355.

    Article  CAS  PubMed  Google Scholar 

  • Brown I, Shalli K, McDonald SL, Moir SE, Hutcheon AW, Heys SD et al. (2004). Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells. Breast Cancer Res 6: R601–R607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caporossi D, Ciafre SA, Pittaluga M, Savini I, Farace MG . (2003). Cellular responses to H2O2 and bleomycin-induced oxidative stress in L6C5 rat myoblasts. Free Radic Biol Med 35: 1355–1364.

    Article  CAS  PubMed  Google Scholar 

  • Carew JS, Huang P . (2002). Mitochondrial defects in cancer. Mol Cancer 1: 9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cavalli LR, Varella-Garcia M, Liang BC . (1997). Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth Differ 8: 1189–1198.

    CAS  PubMed  Google Scholar 

  • Crown J, O'Leary M . (2000). The taxanes: an update. Lancet 355: 1176–1178.

    Article  CAS  PubMed  Google Scholar 

  • Higuchi M, Aggarwal BB, Yeh ET . (1997). Activation of CPP32-like protease in tumor necrosis factor-induced apoptosis is dependent on mitochondrial function. J Clin Invest 99: 1751–1758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Higuchi M, Kudo T, Suzuki S, Evans TT, Sasaki R, Wada Y et al. (2006). Mitochondrial DNA determines androgen dependence in prostate cancer cell lines. Oncogene 25: 1437–1445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwao-Koizumi K, Matoba R, Ueno N, Kim SJ, Ando A, Miyoshi Y et al. (2005). Prediction of docetaxel response in human breast cancer by gene expression profiling. J Clin Oncol 23: 422–431.

    Article  CAS  PubMed  Google Scholar 

  • Khrapko K, Bodyak N, Thilly WG, van Orsouw NJ, Zhang X, Coller HA et al. (1999). Cell-by-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions. Nucleic Acids Res 27: 2434–2441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Miyoshi Y, Taguchi T, Tamaki Y, Nakamura H, Yodoi J et al. (2005). High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer. Clin Cancer Res 11: 8425–8430.

    Article  CAS  PubMed  Google Scholar 

  • King MP, Attardi G . (1989). Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246: 500–503.

    Article  CAS  PubMed  Google Scholar 

  • Kirkland RA, Franklin JL . (2007). Bax affects production of reactive oxygen by the mitochondria of non-apoptotic neurons. Exp Neurol 204: 458–461.

    Article  CAS  PubMed  Google Scholar 

  • Lee CF, Liu CY, Hsieh RH, Wei YH . (2005). Oxidative stress-induced depolymerization of microtubules and alteration of mitochondrial mass in human cells. Ann NY Acad Sci 1042: 246–254.

    Article  CAS  PubMed  Google Scholar 

  • Li YC, Fung KP, Kwok TT, Lee CY, Suen YK, Kong SK . (2004). Mitochondria-targeting drug oligomycin blocked P-glycoprotein activity and triggered apoptosis in doxorubicin-resistant HepG2 cells. Chemotherapy 50: 55–62.

    Article  CAS  PubMed  Google Scholar 

  • Lievre A, Chapusot C, Bouvier A-M, Zinzindohoue F, Piard F, Roignot P et al. (2005). Clinical value of mitochondrial mutations in colorectal cancer. J Clin Oncol 23: 3517–3525.

    Article  CAS  PubMed  Google Scholar 

  • Liu B, Staren ED, Iwamura T, Appert HE, Howard JM . (2001). Mechanisms of taxotere-related drug resistance in pancreatic carcinoma. J Surg Res 99: 179–186.

    Article  CAS  PubMed  Google Scholar 

  • Matsuyama S, Xu Q, Velours J, Reed JC . (1998). The Mitochondrial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell 1: 327–336.

    Article  CAS  PubMed  Google Scholar 

  • Qian W, Nishikawa M, Haque AM, Hirose M, Mashimo M, Sato E et al. (2005). Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death. Am J Physiol Cell Physiol 289: C1466–C1475.

    Article  CAS  PubMed  Google Scholar 

  • Santamaria G, Martinez-Diez M, Fabregat I, Cuezva JM . (2006). Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase. Carcinogenesis 27: 925–935.

    Article  CAS  PubMed  Google Scholar 

  • Schaaf GJ, Maas RFM, de Groene EM, Fink-Gremmels J . (2002). Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells. Free Radic Res 36: 835–843.

    Article  CAS  PubMed  Google Scholar 

  • Schrijvers D, Vermorken JB . (2005). Taxanes in the treatment of head and neck cancer. Curr Opin Oncol 17: 218–224.

    Article  CAS  PubMed  Google Scholar 

  • Shalli K, Brown I, Heys SD, Schofield AC . (2005). Alterations of beta-tubulin isotypes in breast cancer cells resistant to docetaxel. FASEB J 19: 1299–1301.

    Article  CAS  PubMed  Google Scholar 

  • Shin Y-K, Yoo BC, Chang HJ, Jeon E, Hong S-H, Jung M-S et al. (2005). Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res 65: 3162–3170.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki S, Higuchi M, Proske RJ, Oridate N, Hong WK, Lotan R . (1999). Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase-3 in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells. Oncogene 18: 6380–6387.

    Article  CAS  PubMed  Google Scholar 

  • Wils P, Phung-Ba V, Warnery A, Lechardeur D, Raeissi S, Hidalgo IJ et al. (1994). Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochem Pharmacol 48: 1528–1530.

    Article  CAS  PubMed  Google Scholar 

  • Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ, Linnane AW . (1994). Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett 339: 40–44.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Sanae Yamaguchi (Department of Otolaryngology - Head and Neck Surgery, Hokkaido University Graduate School of Medicine) for her technical assistance. This work was supported by Taiho Pharmaceutical Co. Ltd, Tobacco Settlement at State of Arkansas and NIH grant RO1 CA100846 to MH.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    T Mizumachi, S Suzuki, A Naito, J Carcel-Trullols, T T Evans & M Higuchi

  2. Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    T Mizumachi, S Suzuki, N Oridate, Y Furuta & S Fukuda

  3. Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    P M Spring

Authors
  1. T Mizumachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Carcel-Trullols
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T T Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P M Spring
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Oridate
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Furuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Higuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Higuchi.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mizumachi, T., Suzuki, S., Naito, A. et al. Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells. Oncogene 27, 831–838 (2008). https://doi.org/10.1038/sj.onc.1210681

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210681

Keywords

This article is cited by

Search

Advanced search

Quick links