Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells

Sci Rep. 2016 May 25:6:26803. doi: 10.1038/srep26803.

Abstract

B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. This study focused on determining the effects of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-exposure of Ras-mutated cancer cells to PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively, our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells and hence may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, ras*
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Oximes / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / physiology
  • Proto-Oncogene Proteins c-raf / physiology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / biosynthesis*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Recombinant Proteins / pharmacology
  • Sulfonamides / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Transcription Factor CHOP / physiology
  • Transcription, Genetic / drug effects
  • Vemurafenib
  • ets-Domain Protein Elk-1 / physiology

Substances

  • AZD 6244
  • Benzimidazoles
  • DDIT3 protein, human
  • ELK1 protein, human
  • Imidazoles
  • Indoles
  • Neoplasm Proteins
  • Oximes
  • Protein Kinase Inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • Sulfonamides
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • ets-Domain Protein Elk-1
  • Transcription Factor CHOP
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • dabrafenib