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Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase

Hee Sun Byun1, Minho Won, Kyeong Ah Park

  • 1Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-131, Korea.

Experimental & Molecular Medicine
|May 1, 2008
PubMed

Insights

Rottlerin protects against tumor necrosis factor (TNF)-induced necrosis by inhibiting Nox1 NADPH oxidase. This mechanism, independent of protein kinase C delta (PKC-delta) inhibition, reveals a new target for anti-necrotic therapies.

Area of Science:

  • Cell Biology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • Rottlerin, a protein kinase C delta (PKC-delta) inhibitor, is known to enhance apoptosis via death receptor pathways.
  • The role of rottlerin in regulating necrotic cell death and its underlying mechanisms remain largely unexplored.

Purpose of the Study:

  • To investigate the effect of rottlerin on tumor necrosis factor (TNF)-induced necrosis in murine fibrosarcoma L929 cells.
  • To elucidate the molecular mechanisms by which rottlerin modulates necrotic cell death.

Main Methods:

  • Murine fibrosarcoma L929 cells were treated with rottlerin and/or TNF.
  • Cell death (necrosis and apoptosis) was assessed.
  • Mitochondrial superoxide production, GTP-bound Rac1 activation, and poly(ADP-ribose) polymerase (PARP) activation were measured.

Main Results:

  • Rottlerin protected L929 cells against TNF-induced necrosis.
  • TNF treatment induced mitochondrial superoxide production via Nox1 NADPH oxidase during necrosis.
  • Rottlerin inhibited TNF-induced mitochondrial superoxide production and PARP activation, independent of PKC-delta inhibition.
  • Rottlerin also sensitized cells to apoptosis when co-treated with Hsp90 inhibitor geldanamycin and TNF.

Conclusions:

  • Nox1 NADPH oxidase is a novel molecular target for the anti-necrotic effects of rottlerin.
  • Rottlerin's anti-necrotic activity is mediated by suppressing mitochondrial superoxide production through the inhibition of Nox1 NADPH oxidase.
  • These findings provide new insights into the mechanisms of cell death regulation and potential therapeutic strategies targeting necrosis.

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