MtDNA depleted PC3 cells exhibit Warburg effect and cancer stem cell features

Oncotarget. 2016 Jun 28;7(26):40297-40313. doi: 10.18632/oncotarget.9610.


Reducing mtDNA content was considered as a critical step in the metabolism restructuring for cell stemness restoration and further neoplastic development. However, the connections between mtDNA depletion and metabolism reprograming-based cancer cell stemness in prostate cancers are still lack of studies. Here, we demonstrated that human CRPC cell line PC3 tolerated high concentration of the mtDNA replication inhibitor ethidium bromide (EtBr) and the mtDNA depletion triggered a universal metabolic remodeling process. Failure in completing that process caused lethal consequences. The mtDNA depleted (MtDP) PC3 cells could be steadily maintained in the special medium in slow cycling status. The MtDP PC3 cells contained immature mitochondria and exhibited Warburg effect. Furthermore, the MtDP PC3 cells were resistant to therapeutic treatments and contained greater cancer stem cell-like subpopulations: CD44+, ABCG2+, side-population and ALDHbright. In conclusion, these results highlight the association of mtDNA content, mitochondrial function and cancer cell stemness features.

Keywords: Warburg effect; cancer stem cells; hypoxia; mitochondrial DNA; transcriptome analysis.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Cell Count
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • DNA Replication / drug effects
  • DNA, Mitochondrial / genetics*
  • Ethidium / chemistry
  • Humans
  • Hyaluronan Receptors / metabolism
  • Hypoxia / metabolism
  • Male
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / cytology*
  • Oxygen / chemistry
  • Oxygen Consumption
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • CD44 protein, human
  • DNA, Mitochondrial
  • Hyaluronan Receptors
  • Neoplasm Proteins
  • Ethidium
  • Oxygen