Cardamonin sensitizes tumour cells to TRAIL through ROS- and CHOP-mediated up-regulation of death receptors and down-regulation of survival proteins

Br J Pharmacol. 2012 Feb;165(3):741-53. doi: 10.1111/j.1476-5381.2011.01603.x.

Abstract

Background and purpose: TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer, but development of resistance is a major drawback. Thus agents that can overcome resistance to TRAIL are urgently needed. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) has been shown to affect cell growth by modulating various cell signalling pathways. Hence, we investigated the effect of cardamonin on the actions of TRAIL.

Experimental approach: The effect of cardamonin on TRAIL was measured by plasma membrane integrity, phosphatidylserine exposure, mitochondrial activity, and activation of caspase-8, caspase-9, and caspase-3 in human colon cancer cells.

Key results: Cardamonin potentiated TRAIL-induced apoptosis and this correlated with up-regulation of both the TRAIL death receptor (DR) 4, 5 at mRNA and protein levels. TRAIL-decoy receptor DcR1 was down-regulated by cardamonin. Induction of DRs by cardamonin occurred in a variety of cell types. Gene silencing of the DRs by small interfering RNA (siRNA) abolished the effect of cardamonin on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the DR. Induction of the DR by cardamonin was p53-independent but required CCAAT/enhancer binding protein homologous protein (CHOP); cardamonin induced CHOP, and its silencing by siRNA eliminated the induction of DR5. Cardamonin increased the production of reactive oxygen species (ROS) and quenching ROS abolished its induction of receptors and enhancement of TRAIL-induced apoptosis. Cardamonin also decreased the expression of various cell survival proteins.

Conclusions and implications: Cardamonin potentiates TRAIL-induced apoptosis through ROS-CHOP-mediated up-regulation of DRs, decreased expression of decoy receptor and cell survival proteins. Thus, cardamonin has the potential to make TRAIL more effective as an anticancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line, Tumor
  • Chalcones / pharmacology*
  • Colonic Neoplasms / metabolism*
  • Down-Regulation
  • Humans
  • Reactive Oxygen Species / metabolism
  • Receptors, Death Domain / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Transcription Factor CHOP / metabolism
  • Up-Regulation

Substances

  • Apoptosis Regulatory Proteins
  • Chalcones
  • DDIT3 protein, human
  • Reactive Oxygen Species
  • Receptors, Death Domain
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Transcription Factor CHOP
  • cardamonin