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Published on: January 7, 2019

Potential attenuation of p38 signaling by DDB2 as a factor in acquired TNF resistance

Chun-Ling Sun1, Chuck C-K Chao

  • 1Tumor Biology Laboratory, Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan.

International Journal of Cancer
|February 9, 2005
PubMed

Insights

DNA repair protein DDB2 overexpression confers resistance to tumor necrosis factor-alpha (TNF-alpha) by attenuating p38 MAPK signaling, a key pathway in TNF-alpha-induced apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • DNA repair protein DDB2 previously shown to protect against UV and Fas-induced cell death.
  • DDB2 is overexpressed in cisplatin-selected cells, suggesting a role in drug resistance.
  • The precise molecular mechanism of DDB2's protective function in apoptosis remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which DDB2 influences the apoptotic pathway.
  • To investigate the relationship between DDB2 levels and resistance to tumor necrosis factor-alpha (TNF-alpha).
  • To determine the role of p38 MAPK signaling in DDB2-mediated TNF-alpha resistance.

Main Methods:

  • Utilized cisplatin-selected cells exhibiting cross-resistance to TNF-alpha.
  • Investigated the effect of DDB2 knockdown and overexpression on cellular sensitivity to TNF-alpha.
  • Analyzed p38 MAPK activation and downstream apoptotic signaling (caspase-8) in response to TNF-alpha.
  • Employed p38 MAPK inhibitor (SB202190) to assess its impact on TNF-alpha-induced apoptosis.

Main Results:

  • Cisplatin-selected cells showed cross-resistance to TNF-alpha, inversely proportional to DDB2 levels.
  • TNF-alpha treatment induced p38 MAPK activation, which was reduced in DDB2-overexpressing cells.
  • TNF-alpha-induced apoptosis, including caspase-8 activation, was attenuated in cells with higher DDB2 levels.
  • Inhibition of p38 MAPK signaling mimicked the protective effect of DDB2 against TNF-alpha-induced apoptosis.

Conclusions:

  • p38 MAPK activation is a critical upstream mediator of TNF-alpha-induced apoptosis.
  • Overexpression of DDB2 confers resistance to TNF-alpha by suppressing p38 MAPK signaling.
  • DDB2 plays a significant role in acquired resistance to TNF-alpha-induced cell death.

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