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Query: UMLS:C0026764 (
multiple myeloma
)
36,148
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
IFN-gamma is a cytokine which functions in a wide range of biological activities by inducing a number of early and delayed genes. In murine IL-3-dependent cell lines
BAF
-B03 and 32D, IFN-gamma upregulated bag-1 and bcl-xL gene expression. These cells revealed prolonged cell survival against IL-3-deprivation by IFN-gamma stimulation. In contrast, human
myeloma
cell line RPMI8226, despite expression of IFN-gamma receptor, showed neither induction of their expressions nor prolonged cell survival against serum starvation-induced apoptosis by IFN-gamma stimulation. Gene-transfer-mediated overexpression of BAG-1 protein in
BAF
-B03 cells led to prolonged cell survival against IL-3-deprived apoptosis compared with control
BAF
-B03 transfectants, indicating that levels of BAG-1 expression are crucial for cell survival in
BAF
-B03 cells. Taken together, these studies suggest that induction of anti-apoptotic gene expression is a crucial factor for the anti-apoptotic function of IFN-gamma in IL-3-dependent immature hematopoietic cells.
...
PMID:IFN-gamma upregulates anti-apoptotic gene expression and inhibits apoptosis in IL-3-dependent hematopoietic cells. 934 41
To characterize the biological activity of tocilizumab, a humanized anti-human interleukin-6 receptor (IL-6R) monoclonal antibody, we examined its binding activity to both soluble IL-6R (sIL-6R) and membrane bound IL-6R (mIL-6R) and its neutralizing activity to other IL-6 family cytokines. ELISA assay demonstrated that tocilizumab bound to sIL-6R and inhibited IL-6 binding to sIL-6R in a dose-dependent manner. The dissociation constant (Kd value) for IL-6R was determined to be 2.54+/-0.12 nmol/L by Scatchard analysis. In addition, tocilizumab had the ability to dissociate IL-6 and sIL-6R from their preformed complex. The immune complex of tocilizumab and sIL-6R did not transmit signaling. Moreover, tocilizumab suppressed the IL-6/sIL-6R complex-induced proliferation of human gp130-transfected cell,
BAF
-h130. In addition, tocilizumab had the ability to bind to human IL-6R expressing COS-7 cells and to suppress the growth of the IL-6-dependent
myeloma
cell line, KPMM2. Finally, to analyze the specificity of this antibody, the effects on signal transduction of IL-6 family cytokines such as interleukin-11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) were examined using murine transfectant cell lines (BaF/IL-6R, BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR) that proliferate depending on IL-6, IL-11, OSM, LIF and human CNTF, respectively. Tocilizumab inhibited the proliferation of BaF/IL-6R induced by IL-6, but did not inhibit the proliferation of BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR cells induced by their corresponding cytokines. These lines of evidence indicate that tocilizumab is able to bind to both sIL-6R and mIL-6R and to inhibit IL-6 binding to its receptors, leading to the blockade of the IL-6 signaling through both sIL-6R and mIL-6R, but not block the signaling of other IL-6 family cytokines.
...
PMID:Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. 1610 23
Multiple myeloma
(MM) is an incurable plasma cell malignancy with poor survival. Autophagy, a stress-responsive catabolic process mediated by lysosomal activity, plays a crucial role in the pathophysiology of MM. Growing evidence has indicated that dysregulated microRNAs (miRNAs) are associated with the aberrant autophagy in various human cancers. However, to date, few miRNAs have been reported to directly modulate autophagy in the pathobiology of MM. In this study, we investigated the role of
MIR145-3p
(microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of
MIR145-3p
expression was associated with disease progression in human MM.
MIR145-3p
triggered autophagic flux through direct targeting of
HDAC4
(histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing
HDAC4
recapitulated the effects of
MIR145-3p
, whereas enforced expression of
HDAC4
abrogated the effects of
MIR145-3p
. Furthermore, we showed that suppression of
HDAC4
by
MIR145-3p
resulted in upregulation of the pro-apoptotic protein BCL2L11 and caused MTORC1 inactivation, which in turn led to enhanced autophagy and cell death. Importantly, we demonstrated that
MIR145-3p
mimic could potentiate the anti-MM activity of bortezomib in both
in vitro
and
in vivo
experiments. Overall, our findings indicate that
MIR145-3p
exerted a tumor suppression function in MM by inducing autophagic cell death and suggest that
MIR145-3p
-based targeted therapy would represent a novel strategy for MM treatment.
Abbreviations:
3-MA: 3-methyladenine; 3'-UTR: 3'-untranslated region; 7-AAD: 7-aminoactinomycin D; ACTB: actin beta; ANXA5: annexin A5; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin;
BAF
: bafilomycin A
1
; BCL2L11: BCL2 like 11; Bort: bortezomib; CASP3: caspase 3; CCK-8: Cell Counting Kit-8; CQ: chloroquine; Ct: threshold cycle; ctrl: control; DAPI: 4',6-diamidino-2-phenylindole; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HDAC4: histone deacetylase 4; ISS: International Staging System; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNAs: microRNAs;
MIR145-3p
: microRNA 145-3p; MM:
multiple myeloma
; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PCs: plasma cells; PFS: progression-free survival; qRT-PCR: quantitative reverse transcription PCR; RPS6KB1: ribosomal protein S6 kinase B1; SD: standard deviation; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STV: starvation; TUBB: tubulin beta class I.
...
PMID:
MIR145-3p
promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting
HDAC4
. 3124 29
The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of
multiple myeloma
. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant
multiple myeloma
, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated
BAF
(PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4
CRBN
. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory
multiple myeloma
. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with
multiple myeloma
.
...
PMID:ARID2 is a pomalidomide-dependent CRL4
CRBN
substrate in multiple myeloma cells. 3295 52
