Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stress-activated protein kinases (SAPKs), also known as c-Jun amino-terminal kinases (JNKs), are activated in response to diverse stimuli including DNA damage, heat shock, interleukin-1, tumor necrosis factor-alpha and Fas. Although all these inducers cause apoptosis, whether SAPK/JNK activation is required for apoptosis is controversial. In this study, we demonstrate that ionizing radiation (IR) and dexamethasone (Dex) induce apoptosis in multiple myeloma (MM) derived cell lines, as well as in patient cells. IR-induced apoptosis is associated with activation of SAPK/JNK and p38 kinase, in contrast to Dex-induced apoptosis, which is not associated with activation of stress kinases. Moreover, Dex-induced apoptosis is associated with a significant decrease in the activities of mitogen activated protein kinase (MAPK) and p70S6K, whereas IR-treatment does not alter the activity of these kinases. Both IR and Dex induce poly (ADP ribose) polymerase (PARP) cleavage, a signature event of apoptosis. Finally, interleukin-6 (IL-6) inhibits Dex-induced apoptosis, downregulation of MAP and p70S6K growth kinases and PARP cleavage; in contrast, IL-6 does not inhibit IR-induced apoptosis, activation of SAPK/JNK, and PARP cleavage. Taken together, our findings suggest that SAPK/JNK activation is not required for apoptosis in MM cells, and that there are at least two distinct apoptotic signaling pathways: (i) SAPK/JNK-associated, which is induced by IR and unaffected by IL-6; and (ii) SAPK/JNK-independent, which is induced by Dex, associated with downregulation of MAPK and p70S6K and inhibited by IL-6.
...
PMID:Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. 926 70

Interleukin-6 (IL-6) is a pleiotropic cytokine and acts as a growth factor for murine plasmacytoma and human myeloma. IL-6 activates multiple signal transduction pathways. Among them, signal transducer and activator of transcription3 (STAT3), and the SHP-2-mediated Erk/MAP kinase pathway are important. The roles for the two major pathways in the IL-6-induced growth of B cell hybridoma cells were examined. A mutational analysis of the cytoplasmic domain of exogenously expressed gp130, a signal transducing beta chain of the IL-6 receptor complex, revealed that the proximal 133 amino acid (AA) region of gp130 with the intact Y767 but not Y759 is necessary and sufficient for gp130-signal-induced cell proliferation. Interestingly, no requirement of the Y759-mediated signals, including SHP-2-mediated Erk/MAP kinase pathway, coincided with the failure of SHP-2, Gab1/Gab2, and Erk/MAP kinase activation by IL-6 in MH60 cells. Moreover, we show that another serine/threonine kinase pathway leading to STAT3 Ser727 phosphorylation, which seemed to be derived from the Y767 in the proximal 133 AA residues, is intact in MH60 cells. Since Erk/MAP kinases are known to inhibit the subsequent IL-6-induced STAT3 activation, the impaired activation of Erk/MAP kinases by IL-6 may contribute to the development of B cell neoplasia.
...
PMID:No involvement of Erk/MAP kinases in IL-6-induced proliferation of a B cell hybridoma cell line. 1155 93

The evolutionarily conserved Ras/Raf/MEK/ERK pathway is thought to be essential for proliferation of eukaryotic cells. The human multiple myeloma (MM) cell line 8226 encodes an activated K-ras allele and proliferates without requirement for the main MM growth and survival factor IL-6. Surprisingly, the addition of the MEK1/2 inhibitors PD98059 or U0126 to 8226 cultures at doses that block virtually all ERK1/2 activity had minimal effects on the rapid proliferation of this cell line. In contrast, proliferation of the IL-6-dependent MM cell line, ANBL-6 was blocked by PD98059. Levels of activated forms of the other classical MAP kinases (JNK and p38) were very low during MM cell proliferation and, therefore, do not substitute for the mitogenic activities normally regulated by ERK kinases. These data demonstrate that proliferation of 8226 cells does not require ERK1/2 activity, and suggest that IL-6-independent growth of MM may correlate with independence from a requirement for ERK activity. Other signal transduction pathways that appear to regulate cell cycle progression in these cells were examined.
...
PMID:Proliferation of IL-6-independent multiple myeloma does not require the activity of extracellular signal-regulated kinases (ERK1/2). 1220 79

Multiple Myeloma (MM) is a progressive malignancy with poor prognosis, commonly treated by the use of the glucocorticoid Dexamethasone. Myeloma cells resist Dexamethasone induced apoptosis when exposed to IL-6 or IGF-1, both of which are known to activate several signaling cascades. For the first time, we show the actual contribution of downstream mediators, i.e., activated STAT factors, independent of the contribution of their upstream signaling pathways, on the proliferation and Dexamethasone rescue effects of IL-6 and IGF-1 in Multiple Myeloma. Retroviral transduction of cytokine dependent myeloma cells with activated STAT transcription factor constructs overcomes the cells dependence on cytokines for growth, allowing proliferation even in very low serum levels. However, the rescue of these previously cytokine dependent cells with activated STATs does not result in an increase in resistance to Dexamethasone induced apoptosis. Despite the presence of activated STAT3 and STAT5a, apoptosis is induced upon exposure to micromolar levels of Dexamethasone, and IL-6 or IGF-1 is still required to rescue the cells. The ability of these factors to block apoptosis is abrogated by the addition of PI-3 Kinase specific inhibitors, but not inhibitors that target the MAP Kinase pathway. However, ectopic expression of activated STAT3 results in partial rescue from apoptosis of cells treated with FAS ligand. Our data suggests that mechanisms of resistance to induced apoptosis and cellular proliferation are separate and distinct in cytokine dependent myeloma cells.
...
PMID:Activating mutations in STAT3 and STAT5 differentially affect cellular proliferation and apoptotic resistance in multiple myeloma cells. 1497 30

To look for new candidates for agents to use in maintenance therapy for myeloma patients, the growth inhibitory effects of a 3-hydroxy-3-mehtylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), simvastatin, was analyzed using human myeloma cell lines. Several investigations have indicated growth reduction in certain lineages of cancer cells including one report on myeloma, and inhibitory effects of statins on GTPases and involving MAP-kinases. Most (12 out of 13) myeloma lines examined showed growth inhibition when cultured with various concentrations (1-30 microM) of simvastatin in a dose-dependent manner. Simvastatin in combination with other biological response modifiers such as ATRA or DEX had additional effects on growth. In addition, anti-oxides prevented the simvastatin-induced growth inhibition and apoptosis. Furthermore, myeloma cells treated with simvastatin clearly showed inactivation of various MAP-kinase pathways such as ERK1/2, MEK1/2, JNK, and p38. Based on these findings, statins may be suitable for clinical usage in maintenance therapy for myeloma patients.
...
PMID:Effects of an HMG-CoA reductase inhibitor, simvastatin, on human myeloma cells. 1506 46

We describe the first successful clinical application of a new discovery technology, epitope-mediated antigen prediction (E-MAP), to the investigation of multiple myeloma. Until now, there has been no reliable, systematic method to identify the cognate antigens of paraproteins. E-MAP is a variation of previous efforts to reconstruct the epitopes of paraproteins, with the significant difference that it provides enough epitope sequence data so as to enable successful protein database searches. We first reconstruct the paraprotein's epitope by analyzing the peptides that strongly bind. Then, we compile the data and interrogate the nonredundant protein database, searching for a close match. As a clinical proof-of-concept, we apply this technology to uncovering the protein targets of para-proteins in multiple myeloma (MM). E-MAP analysis of 2 MM paraproteins identified human cytomegalovirus (HCMV) as a target in both. E-MAP sequence analysis determined that one para-protein binds to the AD-2S1 epitope of HCMV glycoprotein B. The other binds to the amino terminus of the HCMV UL-48 gene product. We confirmed these predictions using immunoassays and immunoblot analyses. E-MAP represents a new investigative tool for analyzing the role of chronic antigenic stimulation in B-lymphoproliferative disorders.
...
PMID:Accurate identification of paraprotein antigen targets by epitope reconstruction. 1787 98

Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively.
...
PMID:Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level. 1883 93

Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138(+) MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P < .01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-kappaB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.
...
PMID:MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. 1940 61

The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.
...
PMID:Bortezomib induces autophagic death in proliferating human endothelial cells. 1991 81

Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The second mode of MAF transcription occurred in myelomas with multiple myeloma SET domain (MMSET) translocation. MMSET knockdown decreased MAF transcription and cell viability. A small-molecule screen found an inhibitor of mitogen-activated protein kinase kinase (MEK), which activates extracellular signal-regulated kinase (ERK)-MAP kinases, reduced MAF mRNA in cells representing MMSET or MAF subgroups. ERK activates transcription of FOS, part of the AP-1 transcription factor. By chromatin immunoprecipitation, FOS bound the MAF promoter, and MEK inhibition decreased this interaction. MEK inhibition selectively induced apoptosis in MAF-expressing myelomas, and FOS inactivation was similarly toxic. Reexpression of MAF rescued cells from death induced by MMSET depletion, MEK inhibition, or FOS inactivation. The data presented herein demonstrate that the MEK-ERK pathway regulates MAF transcription, providing molecular rationale for clinical evaluation of MEK inhibitors in MAF-expressing myeloma.
...
PMID:A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression. 2135 59


1 2 Next >>

---