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Mitochondrial dysfunction and nuclear-mitochondrial shuttling of TERT are involved in cell proliferation arrest

Xin-Ying Zhuang1, Yong-Gang Yao

  • 1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.

FEBS Letters
|April 23, 2013
PubMed

Insights

The G-quadruplex ligand DODC effectively inhibits cell growth and induces apoptosis by disrupting mitochondrial function, outperforming TMPyP4 in anti-tumor activity.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • G-quadruplex (G4) structures are involved in various cellular processes.
  • Ligands targeting G4 structures, such as DODC and TMPyP4, can inhibit cell proliferation.
  • TERT, the catalytic subunit of telomerase, can localize to the nucleus or mitochondria.

Purpose of the Study:

  • To compare the efficacy of G4 ligands DODC and TMPyP4 in inhibiting cell growth.
  • To investigate the mechanism of action of DODC and TMPyP4, focusing on TERT localization and mitochondrial function.
  • To determine if DODC's anti-tumor ability is linked to mitochondrial dysfunction.

Main Methods:

  • Cell proliferation assays to compare DODC and TMPyP4.
  • Confocal microscopy to observe nuclear-cytoplasmic shuttling and mitochondrial accumulation of TERT.
  • Mitochondrial function assays, including respiratory function analysis.
  • Apoptosis assays to evaluate cell death induction.

Main Results:

  • DODC demonstrated superior cell growth inhibition compared to TMPyP4.
  • Both ligands induced TERT nuclear-cytoplasmic shuttling and mitochondrial accumulation, independent of oxidative stress.
  • DODC robustly induced apoptosis by significantly perturbing mitochondrial function.
  • Overexpression of TERT did not rescue DODC-induced mitochondrial respiratory impairment.

Conclusions:

  • DODC is a potent G-quadruplex ligand with significant anti-tumor potential.
  • DODC's anti-cancer effects are primarily mediated through the disruption of mitochondrial function.
  • Targeting mitochondrial function represents a key therapeutic strategy for DODC in cancer treatment.

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