PMID- 24489962
OWN - NLM
STAT- MEDLINE
DCOM- 20141006
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - C26 cancer-induced muscle wasting is IKKbeta-dependent and NF-kappaB-independent.
PG  - e87776
LID - 10.1371/journal.pone.0087776 [doi]
LID - e87776
AB  - Existing data suggest that NF-kappaB signaling is a key regulator of 
      cancer-induced skeletal muscle wasting. However, identification of the components 
      of this signaling pathway and of the NF-kappaB transcription factors that regulate 
      wasting is far from complete. In muscles of C26 tumor bearing mice, 
      overexpression of dominant negative (d.n.) IKKbeta blocked muscle wasting by 69% and 
      the IkappaBalpha-super repressor blocked wasting by 41%. In contrast, overexpression of 
      d.n. IKKalpha or d.n. NIK did not block C26-induced wasting. Surprisingly, 
      overexpression of d.n. p65 or d.n. c-Rel did not significantly affect muscle 
      wasting. Genome-wide mRNA expression arrays showed upregulation of many genes 
      previously implicated in muscle atrophy. To test if these upregulated genes were 
      direct targets of NF-kappaB transcription factors, we compared genome-wide p65 
      binding to DNA in control and cachectic muscle using ChIP-sequencing. 
      Bioinformatic analysis of ChIP-sequencing data from control and C26 muscles 
      showed very little p65 binding to genes in cachexia and little to suggest that 
      upregulated p65 binding influences the gene expression associated with muscle 
      based cachexia. The p65 ChIP-seq data are consistent with our finding of no 
      significant change in protein binding to an NF-kappaB oligonucleotide in a gel shift 
      assay, no activation of a NF-kappaB-dependent reporter, and no effect of d.n.p65 
      overexpression in muscles of tumor bearing mice. Taken together, these data 
      support the idea that although inhibition of IkappaBalpha, and particularly IKKbeta, blocks 
      cancer-induced wasting, the alternative NF-kappaB signaling pathway is not required. 
      In addition, the downstream NF-kappaB transcription factors, p65 and c-Rel do not 
      appear to regulate the transcriptional changes induced by the C26 tumor. These 
      data are consistent with the growing body of literature showing that there are 
      NF-kappaB-independent substrates of IKKbeta and IkappaBalpha that regulate physiological 
      processes.
FAU - Cornwell, Evangeline W
AU  - Cornwell EW
AD  - Department of Health Sciences, Boston University, Boston, Massachusetts, United 
      States of America.
FAU - Mirbod, Azadeh
AU  - Mirbod A
AD  - Department of Health Sciences, Boston University, Boston, Massachusetts, United 
      States of America.
FAU - Wu, Chia-Ling
AU  - Wu CL
AD  - Department of Health Sciences, Boston University, Boston, Massachusetts, United 
      States of America.
FAU - Kandarian, Susan C
AU  - Kandarian SC
AD  - Department of Health Sciences, Boston University, Boston, Massachusetts, United 
      States of America.
FAU - Jackman, Robert W
AU  - Jackman RW
AD  - Department of Health Sciences, Boston University, Boston, Massachusetts, United 
      States of America.
LA  - eng
GR  - R01 AR060217/AR/NIAMS NIH HHS/United States
GR  - AR060217/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140129
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Rela protein, mouse)
RN  - 0 (Transcription Factor RelA)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Adenocarcinoma/*metabolism
MH  - Animals
MH  - Cachexia/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Ontology
MH  - I-kappa B Kinase/*metabolism
MH  - Male
MH  - Mice
MH  - Muscle, Skeletal/metabolism/pathology
MH  - Muscular Atrophy/*metabolism
MH  - Neoplasm Transplantation
MH  - Oligonucleotide Array Sequence Analysis
MH  - Transcription Factor RelA/*metabolism
MH  - Transcriptome
PMC - PMC3906224
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/02/04 06:00
MHDA- 2014/10/07 06:00
PMCR- 2014/01/29
CRDT- 2014/02/04 06:00
PHST- 2013/07/09 00:00 [received]
PHST- 2013/12/30 00:00 [accepted]
PHST- 2014/02/04 06:00 [entrez]
PHST- 2014/02/04 06:00 [pubmed]
PHST- 2014/10/07 06:00 [medline]
PHST- 2014/01/29 00:00 [pmc-release]
AID - PONE-D-13-28335 [pii]
AID - 10.1371/journal.pone.0087776 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 29;9(1):e87776. doi: 10.1371/journal.pone.0087776. eCollection 
      2014.