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Rap1 is indispensable for TRF2 function in etoposide-induced DNA damage response in gastric cancer cell line

X Li1, W Liu2, H Wang2

  • 1Department of Neurology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Oncogenesis
|March 31, 2015
PubMed

Insights

Rap1, a protein interacting with TRF2, plays a key role in gastric cancer cells' resistance to etoposide. Silencing Rap1 reverses this resistance by restoring ATM-dependent DNA damage response pathways.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Telomeric repeat-binding factor 2 (TRF2) is implicated in DNA damage response and multidrug resistance (MDR) in gastric cancer.
  • Rap1 is a TRF2-interacting protein crucial for telomere protection.
  • The role of Rap1 in TRF2-mediated drug resistance remains unclear.

Purpose of the Study:

  • To investigate the effect of Rap1 on TRF2 function in DNA damage response induced by anticancer drugs.
  • To elucidate the mechanism by which Rap1 influences etoposide resistance in gastric cancer cells.

Main Methods:

  • Utilized gastric cancer cell lines (SGC7901 and SGC7901/VCR) treated with etoposide.
  • Employed siRNA to silence Rap1 expression.
  • Assessed protein expression and phosphorylation levels of TRF2, Rap1, ATM, γH2AX, and p53.

Main Results:

  • Both Rap1 and TRF2 expression increased following etoposide treatment, notably in the MDR variant.
  • Rap1 silencing partially reversed etoposide resistance and TRF2-mediated resistance.
  • Rap1 silencing restored ATM expression and phosphorylation, leading to increased phosphorylation of ATM targets like γH2AX and p53.

Conclusions:

  • Rap1 interacts with TRF2 and significantly contributes to TRF2-mediated DNA damage response and etoposide resistance in gastric cancer.
  • Rap1's function involves regulating ATM activation, thereby influencing cellular response to chemotherapy.

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