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TRF2 promotes multidrug resistance in gastric cancer cells

Hanbing Ning1, Tingting Li, Lina Zhao

  • 1State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China.

Cancer Biology & Therapy
|June 9, 2006
PubMed

Insights

The study reveals that TRF2, a DNA-binding factor, plays a crucial role in gastric cancer drug resistance by influencing DNA damage response pathways. Upregulation of TRF2 is linked to multidrug resistance, suggesting it as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The role of telomeres and associated proteins in drug resistance remains unclear.
  • DNA double-strand breaks (DSBs) trigger responses involving proteins like TRF2, potentially impacting DNA repair.
  • Previous findings on telomerase activity and telomere length in drug resistance are controversial.

Purpose of the Study:

  • To investigate the involvement of telomerase, telomere length, and TRF2 in DNA damage response and drug resistance in gastric cancer.
  • To elucidate the specific role of TRF2 in the context of multidrug resistance.

Main Methods:

  • Utilized multidrug-resistant gastric cancer cell lines (SGC7901 variants).
  • Assessed telomere length, telomerase activity, and expression of TRF1 and TRF2 following treatment with adriamycin or etoposide.
  • Examined the expression of DNA damage response markers (ATM, gammaH2AX, p53).
  • Employed RNA interference (RNAi) to inhibit TRF2 expression and assessed changes in drug resistance phenotype.
  • Overexpressed TRF2 to evaluate its effect on drug resistance.

Main Results:

  • Telomere length was elongated in resistant cells but not directly affected by drug treatment alone.
  • Telomerase activity and TRF2 expression were upregulated post-treatment, with TRF2 showing a more dramatic increase in resistant cells.
  • TRF2 upregulation preceded the expression of key DNA damage response proteins (ATM, gammaH2AX, p53).
  • TRF2 inhibited the expression of ATM-dependent DSB responsive genes.
  • TRF2 inhibition partially reversed drug resistance, while its overexpression promoted resistance.

Conclusions:

  • TRF2 is significantly involved in the DNA damage response and plays a critical role in gastric cancer drug resistance.
  • TRF2 acts as a key factor in mediating resistance, potentially by modulating the ATM-dependent DNA damage response.
  • Targeting TRF2 may offer a novel strategy to overcome multiple drug resistance in gastric cancer.

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