PMID- 22898869
OWN - NLM
STAT- MEDLINE
DCOM- 20121108
LR  - 20211203
IS  - 2041-4889 (Electronic)
VI  - 3
IP  - 8
DP  - 2012 Aug 16
TI  - Restored expression of the atypical heat shock protein H11/HspB8 inhibits the 
      growth of genetically diverse melanoma tumors through activation of novel 
      TAK1-dependent death pathways.
PG  - e371
LID - 10.1038/cddis.2012.108 [doi]
AB  - Melanoma is an aggressive and drug-resistant cancer in need of improved 
      therapeutic strategies. Restored expression of transcriptionally silenced genes 
      is a potential approach, but it is limited by the genetic diversity of the 
      melanoma tumors. The atypical heat shock protein H11/HspB8 has kinase activity 
      and is silenced in melanoma through aberrant DNA methylation. We report that its 
      restored expression induces the death of genetically diverse melanoma lines and 
      inhibits tumor growth through the activation of novel TAK1-dependent death 
      pathways. These include (i) caspase-1 activation independent of the inflammasome 
      through upregulation of apoptosis-associated speck-like protein containing a CARD 
      (ASC), (ii) Beclin-1 upregulation through phosphorylation of mammalian target of 
      rapamycin (mTOR) at S2481 and (iii) apoptosis caused by caspase-1-mediated 
      Beclin-1 cleavage. These data extend current understanding of cell 
      death-associated functions, underscore the strong therapeutic promise of 
      H11/HspB8 and identify TAK1 as a potential intervention target in melanoma.
FAU - Smith, C C
AU  - Smith CC
AD  - Department of Pharmacology, University of Maryland, School of Medicine, 
      Baltimore, MD 21201-1559, USA.
FAU - Lee, K S
AU  - Lee KS
FAU - Li, B
AU  - Li B
FAU - Laing, J M
AU  - Laing JM
FAU - Hersl, J
AU  - Hersl J
FAU - Shvartsbeyn, M
AU  - Shvartsbeyn M
FAU - Aurelian, L
AU  - Aurelian L
LA  - eng
GR  - R01 AR053512/AR/NIAMS NIH HHS/United States
GR  - AR053512/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120816
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BECN1 protein, human)
RN  - 0 (Beclin-1)
RN  - 0 (CARD Signaling Adaptor Proteins)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (HSPB8 protein, human)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Inflammasomes)
RN  - 0 (Membrane Proteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (PYCARD protein, human)
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP kinase kinase kinase 7)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/toxicity
MH  - Apoptosis/drug effects
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Beclin-1
MH  - CARD Signaling Adaptor Proteins
MH  - Caspase 1/metabolism
MH  - Cell Line, Tumor
MH  - Cytoskeletal Proteins/metabolism
MH  - DNA Methylation
MH  - Doxorubicin/toxicity
MH  - Heat-Shock Proteins/*metabolism
MH  - Humans
MH  - Inflammasomes/metabolism
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - Melanoma/genetics/metabolism/pathology
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Molecular Chaperones
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transplantation, Heterologous
MH  - Up-Regulation
PMC - PMC3434666
EDAT- 2012/08/18 06:00
MHDA- 2012/11/09 06:00
PMCR- 2012/08/01
CRDT- 2012/08/18 06:00
PHST- 2012/08/18 06:00 [entrez]
PHST- 2012/08/18 06:00 [pubmed]
PHST- 2012/11/09 06:00 [medline]
PHST- 2012/08/01 00:00 [pmc-release]
AID - cddis2012108 [pii]
AID - 10.1038/cddis.2012.108 [doi]
PST - epublish
SO  - Cell Death Dis. 2012 Aug 16;3(8):e371. doi: 10.1038/cddis.2012.108.