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Inhibitory Role of TRIP-Br1/XIAP in Necroptosis under Nutrient/Serum Starvation

Zolzaya Sandag1,2, Samil Jung1,2, Nguyen Thi Ngoc Quynh1

  • 1Department of Biological Science, Sookmyung Women's University, Seoul 14310, Korea.

Molecules and Cells
|February 14, 2020
PubMed

Insights

Cancer cells resist apoptosis, so researchers explored inducing necroptosis. TRIP-Br1/XIAP suppresses necroptosis by inhibiting reactive oxygen species and mitochondrial CypD export, acting as an oncoprotein.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Many anti-cancer therapies target apoptosis, but cancer cells develop resistance.
  • Alternative cell death pathways, like necroptosis, are crucial for overcoming resistance.
  • Understanding mechanisms that inhibit necroptosis is vital for developing new cancer treatments.

Purpose of the Study:

  • Investigate the inhibitory role of TRIP-Br1/XIAP in necroptosis under nutrient/serum starvation.
  • Determine how TRIP-Br1/XIAP affects reactive oxygen species generation and mitochondrial pathways in necroptosis.
  • Explore the potential of targeting TRIP-Br1/XIAP to enhance anti-cancer strategies.

Main Methods:

  • Induction of necroptosis in nine cancer cell lines under prolonged serum starvation.
  • Analysis of TRIP-Br1 oncogenic protein levels and its correlation with necroptosis.
  • Measurement of reactive oxygen species generation and XIAP phosphorylation.
  • Mitochondrial fractionation to assess TRIP-Br1 localization and CypD export.
  • Testing the effect of TRIP-Br1 on shikonin- and TNF-α-mediated necroptosis.

Main Results:

  • Necroptosis was significantly induced in most tested cancer cell lines by serum starvation.
  • MCF-7 cells, resistant to apoptosis, showed lower necroptosis induction and high TRIP-Br1 levels.
  • Upregulated TRIP-Br1 suppressed necroptosis by reducing reactive oxygen species and inhibiting mitochondrial CypD export.
  • XIAP enhanced TRIP-Br1's suppression of necroptosis, partly via increased XIAP phosphorylation.
  • TRIP-Br1 suppressed shikonin-mediated necroptosis but not TNF-α-mediated necroptosis.

Conclusions:

  • TRIP-Br1/XIAP acts as an oncoprotein by suppressing necroptosis in cancer cells during nutrient/serum starvation.
  • Targeting TRIP-Br1/XIAP may represent a novel strategy to re-sensitize resistant cancer cells to cell death.
  • The differential effect of TRIP-Br1 on various necroptosis pathways suggests complex regulatory mechanisms.
Keywords:
TRIP-Br1XIAPnecroptosisprogrammed cell death

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