PMID- 27222248
OWN - NLM
STAT- MEDLINE
DCOM- 20180409
LR  - 20181202
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 6
DP  - 2016 May 25
TI  - Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances 
      DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells.
PG  - 26803
LID - 10.1038/srep26803 [doi]
LID - 26803
AB  - 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.
FAU - Oh, You-Take
AU  - Oh YT
AD  - Department of Hematology and Medical Oncology, Emory University School of 
      Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
FAU - Deng, Jiusheng
AU  - Deng J
AD  - Department of Hematology and Medical Oncology, Emory University School of 
      Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
FAU - Yue, Ping
AU  - Yue P
AD  - Department of Hematology and Medical Oncology, Emory University School of 
      Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
FAU - Sun, Shi-Yong
AU  - Sun SY
AD  - Department of Hematology and Medical Oncology, Emory University School of 
      Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160525
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (AZD 6244)
RN  - 0 (Benzimidazoles)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (ELK1 protein, human)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Oximes)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Sulfonamides)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFRSF10B protein, human)
RN  - 0 (TNFSF10 protein, human)
RN  - 0 (ets-Domain Protein Elk-1)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 207SMY3FQT (Vemurafenib)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - QGP4HA4G1B (dabrafenib)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Benzimidazoles/pharmacology
MH  - Cell Line, Tumor
MH  - Enzyme Activation/drug effects
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - *Genes, ras
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Indoles/*pharmacology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Neoplasm Proteins/*biosynthesis/genetics
MH  - Oximes/pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/physiology
MH  - Proto-Oncogene Proteins c-raf/physiology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*biosynthesis/genetics
MH  - Recombinant Proteins/pharmacology
MH  - Sulfonamides/*pharmacology
MH  - TNF-Related Apoptosis-Inducing Ligand/pharmacology
MH  - Transcription Factor CHOP/physiology
MH  - Transcription, Genetic/drug effects
MH  - Vemurafenib
MH  - ets-Domain Protein Elk-1/physiology
PMC - PMC4879700
EDAT- 2016/05/26 06:00
MHDA- 2018/04/10 06:00
PMCR- 2016/05/25
CRDT- 2016/05/26 06:00
PHST- 2016/03/08 00:00 [received]
PHST- 2016/05/10 00:00 [accepted]
PHST- 2016/05/26 06:00 [entrez]
PHST- 2016/05/26 06:00 [pubmed]
PHST- 2018/04/10 06:00 [medline]
PHST- 2016/05/25 00:00 [pmc-release]
AID - srep26803 [pii]
AID - 10.1038/srep26803 [doi]
PST - epublish
SO  - Sci Rep. 2016 May 25;6:26803. doi: 10.1038/srep26803.