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

T Mizumachi1, S Suzuki, A Naito

  • 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72005, USA.

Oncogene
|July 20, 2007
PubMed

Insights

Mitochondrial DNA (mtDNA) increases docetaxel resistance in laryngeal cancer cells by upregulating Fo-ATPase. This mechanism reduces reactive oxygen species (ROS) generation, inhibiting docetaxel-induced cell death and promoting chemoresistance.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Docetaxel is a key chemotherapy drug, but cancer cells can develop resistance.
  • The mechanisms underlying docetaxel resistance, particularly involving mitochondria, are not fully understood.

Purpose of the Study:

  • To investigate the roles of mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) in docetaxel resistance.
  • To elucidate the specific mitochondrial components involved in acquired docetaxel resistance.

Main Methods:

  • Generation of a docetaxel-resistant cell line (DRHEp2) from human laryngeal cancer cells (HEp2).
  • Assessment of mtDNA content and its manipulation using ethidium bromide.
  • Inhibition of mitochondrial respiratory chain (MRC) complexes, including Fo-ATPase, using specific inhibitors (Oligomycin A) and RNA interference.
  • Measurement of ROS generation and its modulation by antioxidants (pyrrolidine dithiocarbamate).

Main Results:

  • DRHEp2 cells exhibited significantly increased mtDNA content compared to parental HEp2 cells.
  • Reducing mtDNA content in DRHEp2 cells decreased their docetaxel resistance.
  • Inhibition of Fo-ATPase, but not other MRC components, abolished docetaxel resistance in DRHEp2 cells.
  • Docetaxel-induced ROS generation was diminished in DRHEp2 cells, and its inhibition was linked to Fo-ATPase activity.
  • Inhibition of Fo-ATPase restored docetaxel-induced ROS generation and cytotoxicity in resistant cells.

Conclusions:

  • Increased mtDNA content and subsequent upregulation of Fo-ATPase are critical for acquired docetaxel resistance.
  • The Fo-ATPase-mediated mechanism involves the reduction of ROS generation, which impairs docetaxel's cytotoxic effects.
  • Targeting mtDNA and Fo-ATPase presents a potential strategy to overcome docetaxel resistance in laryngeal cancer.

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