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Indirubin enhances tumor necrosis factor-induced apoptosis through modulation of nuclear factor-kappa B signaling

Gautam Sethi1, Kwang Seok Ahn, Santosh K Sandur

  • 1Cytokine Research Laboratory, Department of Experimental Therapeutics, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

The Journal of Biological Chemistry
|June 21, 2006
PubMed

Insights

Indirubin, a compound with known anti-cancer effects, suppresses the nuclear factor kappa B (NF-kappaB) pathway. This mechanism explains its anti-inflammatory and anti-cancer activities by inhibiting key signaling molecules and gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • Indirubin exhibits anti-cancer and anti-inflammatory properties.
  • The precise mechanism of indirubin's action remains largely unelucidated.
  • The nuclear factor kappa B (NF-kappaB) pathway is a critical regulator of inflammation and cancer.

Purpose of the Study:

  • To investigate if indirubin's effects are mediated through the NF-kappaB pathway.
  • To elucidate the molecular targets of indirubin within the NF-kappaB signaling cascade.

Main Methods:

  • Assessed NF-kappaB DNA binding and reporter activity.
  • Examined the effects of indirubin on IkappaB alpha phosphorylation and degradation.
  • Investigated indirubin's impact on NF-kappaB-regulated gene expression.
  • Evaluated indirubin's influence on apoptosis and cellular invasion.

Main Results:

  • Indirubin dose- and time-dependently suppressed TNF-induced NF-kappaB activation.
  • Indirubin inhibited NF-kappaB activation triggered by various inflammatory agents and carcinogens.
  • Indirubin blocked IkappaB alpha phosphorylation and degradation by inhibiting IKK.
  • Indirubin reduced the expression of NF-kappaB-regulated genes involved in anti-apoptosis, proliferation, and invasion.
  • Indirubin enhanced TNF- and taxol-induced apoptosis and suppressed cytokine-induced invasion.

Conclusions:

  • Indirubin's anti-cancer and anti-inflammatory activities are, in part, mediated by the suppression of the NF-kappaB pathway.
  • Indirubin interferes with upstream signaling components of the NF-kappaB pathway, including IKK.
  • Indirubin's inhibition of NF-kappaB leads to reduced expression of oncogenic and pro-inflammatory genes.

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