scholarly journals Dissecting the Biological Relevance and Clinical Impact of lncRNA MIAT in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5518
Author(s):  
Katia Todoerti ◽  
Domenica Ronchetti ◽  
Noemi Puccio ◽  
Ilaria Silvestris ◽  
Vanessa Favasuli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Ribosome Biogenesis ◽  
Multivariate Analyses ◽  
Clinical Impact ◽  
Biological Impact ◽  
Pathogenetic Role ◽  
Expression Levels ◽  
Non Coding Rnas ◽  
Translational Process

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an essential aspect of the investigation, which may contribute to understanding the disease’s complex pathobiology, providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the clinical relevance of the lncRNA MIAT in MM, taking advantage of the publicly available CoMMpass database. MIAT expression in MM is highly heterogeneous and significantly associated with specific molecular lesions frequently occurring in MM. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of MIAT in different signaling pathways and ribosome biogenesis and assembly. These findings suggest that MIAT deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and, indirectly, the translational process. Although MIAT expression levels seem not to be significantly associated with clinical outcome in multivariate analyses, high MIAT expression levels are associated with bortezomib resistance, this suggesting that MIAT targeting could overcome drug resistance in MM. These findings strongly prompt for further studies investigating the significance of MIAT in MM.

scholarly journals MicroRNAs-Based Nano-Strategies as New Therapeutic Approach in Multiple Myeloma to Overcome Disease Progression and Drug Resistance

2020 ◽  
Vol 21 (9) ◽  
pp. 3084 ◽  
Author(s):  
Vanessa Desantis ◽  
Ilaria Saltarella ◽  
Aurelia Lamanuzzi ◽  
Assunta Melaccio ◽  
Antonio Giovanni Solimando ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Tumor Suppressors ◽  
Therapeutic Approach ◽  
Physical Stability ◽  
Cellular Processes ◽  
Non Coding Rnas ◽  
Potential Use ◽  
Nuclease Degradation

MicroRNAs (miRNAs, or miRs) are single-strand short non-coding RNAs with a pivotal role in the regulation of physiological- or disease-associated cellular processes. They bind to target miRs modulating gene expression at post-transcriptional levels. Here, we present an overview of miRs deregulation in the pathogenesis of multiple myeloma (MM), and discuss the potential use of miRs/nanocarriers association in clinic. Since miRs can act as oncogenes or tumor suppressors, strategies based on their inhibition and/or replacement represent the new opportunities in cancer therapy. The miRs delivery systems include liposomes, polymers, and exosomes that increase their physical stability and prevent nuclease degradation. Phase I/II clinical trials support the importance of miRs as an innovative therapeutic approach in nanomedicine to prevent cancer progression and drug resistance. Results in clinical practice are promising.

scholarly journals Inhibition of apoptosis may lead to the development of bortezomib resistance in multiple myeloma cancer cells

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Emine Öksüzoğlu ◽  
Gül Kozalak
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Plasma Cells ◽  
Expression Levels ◽  
Diphenyltetrazolium Bromide ◽  
Apoptotic Pathways ◽  
Resistant Cells

AbstractBackgroundMultiple myeloma (MM), a malignancy of plasma cells, is the second most prevalent hematological cancer. Bortezomib is the most effective chemotherapeutic drug used in treatment. However, drug-resistance prevents success of chemotherapy. One of the factors causing drug-resistance is dysfunction of apoptotic-pathways. This study aimed to evaluate the relationship between expression levels of Bcl-2, Bax, caspase-3 and p-53 genes involved in apoptosis and the development of bortezomib-resistance in MM cell lines.Materials and methodsMultiple myeloma KMS20 (bortezomib-resistant) and KMS28 (bortezomib-sensitive) cell lines were used. 3-[4,5-Dimethylthiazol-2-yl] 1-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine IC50 values of bortezomib. RNAs were isolated from bortezomib-treated cell lines, followed by cDNA synthesis. Expression levels of the genes were analyzed by using q-Realtime-PCR.ResultsAs a result, Bcl-2/Bax ratio was higher in KMS20 (resistant) cells than in KMS28 (sensitive) cells. Expression of caspase-3 decreased in KMS20-cells, whereas increased in KMS28-cells. The results indicate that apoptosis was suppressed in resistant cells.ConclusionThese findings will enable us to understand the molecular mechanisms leading to drug-resistance in MM cells and to develop new methods to prevent the resistance. Consequently, preventing the development of bortezomib resistance by eliminating the factors which suppress apoptosis may be a new hope for MM treatment.

Targeting Neddylation to Overcome Drug Resistance in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1804-1804
Author(s):  
Gregory S Thomas ◽  
Junwei Huang ◽  
Yi Zhou ◽  
Zhimin Gu ◽  
Ye Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Clinical Outcomes ◽  
Colony Formation ◽  
Soft Agar ◽  
Cell Sensitivity ◽  
Expression Levels ◽  
Proteasomal Inhibition ◽  
Elevated Expression

Abstract Background: The overexpression of CKS1B resulting from chromosomal amplification of the 1q21 region identifies a subset of multiple myeloma (MM) patients with poor clinical outcomes. Bortezomib (Btz) is an FDA-approved first-in-class proteasome inhibitor that has greatly improved clinical outcomes in MM. However, toxicities affiliated with pan-proteasomal inhibition and resistant populations remain a problem, highlighting the need for improved therapies. We have previously demonstrated that elevated expression of CKS1B results in the destabilization of p21 and contributes to insensitivity to bortezomib. MLN4924 is an inhibitor of the NEDD8-Activating Enzyme E1 (NAE1) and prevents the neddylation and subsequent activation of Cullin-1, a crucial component in the activation of SCF-driven ubiquitin-mediated degradation. We therefore explored if MLN4924 might serve as an alternative inhibitor to proteasomal degradation in MM. Materials and Methods: CKS1B was overexpressed or knocked down in myeloma cell lines using lentiviral vectors and shRNA. Cell proliferation and viability were assessed by cell counts and using PrestoBlue reagent. Clonogenicity was assessed by colony formation in soft agar. SA-b-galactosidase staining was used to assess senescence. Gene expression profiling was performed using the publicly available databases Total Therapy 2 (TT2) and APEX trials. Results: To examine the efficacy of Btz and MLN4924 in elevated CKS1B expression environments, we compared treatment with the MLN4924 to Btz in CKS1B OE cells in vitro. Cells with basal levels of CKS1B were sensitive to treatment with either Btz or MLN4924, with treatment leading to decreased proliferation and cellular viability. In the CKS1B OE background, we found cells were resistant to Btz repression of proliferation but sensitive to MLN4924. We also found that MLN4924 could more potently reduce colony formation in soft agar and more potently induce senescence in CKS1B OE cells compared to treatment with Btz. Immunoblot analyses confirmed a correlation between CKS1B expression and Cullin-1 neddylation. Further immunoblotting of known SCF-mediated ubiquitin targets in cells with and without CKS1B OE demonstrated a stabilization of p21 in all cells upon MLN4924 treatment that was not exhibited upon Btz treatment. To investigate the role of p21 in CKS1BOE cell sensitivity to MLN4924, we stably knocked down expression of p21. We found the knockdown of p21 partially abrogated the sensitivity of CKS1B OE cells to MLN4924, increasing cell viability, increasing colony formation in soft agar, and decreasing senescence induction. The importance of neddylation in the clinic was confirmed using GEP. We found that expression of the neddylation-related genes (i.e. NAE1, UBA3, and UBC12) is significantly upregulated (p<0.05) in MM patients relative to patients in MGUS or to healthy donors. Expression of NEDD8 was also significantly elevated in patients unresponsive to either Btz treatment or treatment with the combination of Btz and dexamethasone compared to responsive patients. The elevated expression of CKS1B highlights a population of patients with poor clinical outcomes. Considering the elevated expression of neddylation-related genes in MM progression, we performed Kaplan Meier survival analyses looking at patients segregated on two axes by CKS1B expression levels (high/low) and neddylation-related gene expression levels (either UBA3 or UBC12). We found patients with high/high expression of CKS1B and neddylation-related genes had significantly decreased survival relative to patients with mixed high/low expression from either axis. Together, these data suggest the importance of neddylation contributions to MM progression and clinical outcomes. Conclusions: These results shed light on the subtle differences in the blockade of proteasomal inhibition, illustrating the distinct effects of pan inhibition from inhibition of SCF-driven ubiquitin-mediated degradation. Mechanistically, we demonstrate at least a partial role for p21 in mediating cell sensitivity to MLN4924 in CKS1B overexpressing cells. Our findings highlight the important contributions of neddylation to MM disease progression and suggest the utility of targeting neddylation as a means of overcoming drug resistance in MM. Disclosures No relevant conflicts of interest to declare.

Higher Expression Levels of the Adhesion Molecules VLA-4 and ICAM-1 on Multiple Myeloma Cells after Chemotherapy Are Associated with Survival of a Multidrug Resistant Subpopulation in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4866-4866
Author(s):  
Ralf Schmidmaier ◽  
Kerstin Mörsdorf ◽  
Philipp Baumann ◽  
Bertold Emmerich ◽  
Gerold Meinhardt
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Adhesion Molecules ◽  
Stromal Cells ◽  
High Dose ◽  
Myeloma Cells ◽  
Expression Levels ◽  
Before And After ◽  
Primary Drug

Abstract Objectives: Primary drug resistance is a major problem in multiple myeloma (MM), an incurable disease of the bone marrow. Adhesion of multiple myeloma cells to bone marrow stromal cells (BMSC) has been shown to cause strong primary resistance. The adhesion molecules LFA-1 and VLA-4 are upregulated upon treatment with cytotoxic agents. Furthermore, we have shown that the corresponding ligands on HS-5 BMSCs, VCAM-1 and ICAM-1, are upregulated after incubation with melphalan, suggesting increase of adhesion mediated drug resistance after chemotherapy. In this context, the expression levels of important adhesion molecules on MM cells of consecutive MM patients before and after chemotherapy have been determined in this study. Methods: The expression levels of VLA-1, VLA-4, VLA-5, LFA-1, VCAM, ICAM-1, CD138, CD38, and CD56 were determined on MM cell lines, HS-5 stromal cells, and primary myeloma cells of 20 consecutive patients by flow cytometry in comparison to isotype control. 9 patients had been pre-treated (mostly induction chemotherapy and high dose melphalan with stem cell rescue) and 11 patients had been at diagnosis without treatment. Interpatient comparison of treated and untreated patients was performed. Intrapatient analysis (before and after high dose chemotherapy) will be performed in the follow up. Results: VLA-4 and ICAM-1 are upregulated after chemotherapy by 54% and 64%, respectively. Similar upregulation of CD38 could be observed (62%), whereas CD138 shows downregulation by about 50%. CD56, VCAM, and LFA-1 expression was not significantly altered after chemotherapy. Conclusion: The adhesion molecules VLA-4 and ICAM-1, which are essential for MM-BMSC interaction, are upregulated after chemotherapy. This finding supports our preclinical data and the hypothesis, that adhered, primary drug resistant MM cells are selected by chemotherapy and herewith contribute to multidrug resistance in multiple myeloma.

scholarly journals Evidence for Cell Adhesion-Mediated Drug Resistance of Multiple Myeloma Cells in Vivo

2006 ◽  
Vol 21 (4) ◽  
pp. 218-222 ◽  
Author(s):  
R. Schmidmaier ◽  
K. Mörsdorf ◽  
P. Baumann ◽  
B. Emmerich ◽  
G. Meinhardt
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Myeloma Cells ◽  
Expression Levels

Background/Aims Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry. Methods A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules. Results ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders. Conclusion This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.

scholarly journals Potential Crosstalk of Interleukin-6-Heme Oxygenase-1 Dependent Mechanism Involved in Resistance to Lenalidomide in Multiple Myeloma Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4856-4856
Author(s):  
Jishi Wang ◽  
Weibing Wu ◽  
Dan Ma ◽  
Ping Wang ◽  
Lu Cao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Mrna Expression ◽  
Heme Oxygenase ◽  
Interleukin 6 ◽  
Conflicts Of Interest ◽  
Janus Kinase ◽  
Heme Oxygenase 1 ◽  
Expression Levels

Abstract Interleukin-6 (IL-6), as one of the most important multiple myeloma (MM) survival factors, has been verified to determine poor prognosis of MM. IL-6 mainly originates from paracrine of bone marrow stromal cells and autocrine of MM cells. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. The HO-1 expression levels in bone marrow CD138+ cells of MM patients, which were significantly higher than those of healthy donors, were positively correlated with serum IL-6 levels and intracellular IL-6 mRNA expression levels. Cultivating U266 and CD138+ cells with exogenous IL-6 in vitro induced high HO-1 expressions and allowed them to resist lenalidomide, probably because IL-6 activated the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Without IL-6 co-culture, on the other hand, up-regulating HO-1 expressions in U266 cells and bone marrow CD138+ cells from MM patients significantly up-regulated the mRNA expression level of IL-6 and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced of p38 MAPK phosphorylation. Down-regulating HO-1 expression sensitized U266 and CD138+ cells toward lenalidomide. Therefore, we postulated that HO-1 predominantly controlled IL-6 paracrine and autocrine, and that IL-6 in bone marrow microenvironment of MM patients stimulated MM cells to highly express HO-1 and to resist lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, thus further augmenting the drug resistance and exacerbating the disease. This study provides valuable experimental evidence for using HO-1 as a possible marker for MM prognosis and drug resistance and as a potential treatment target. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

scholarly journals Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2878
Author(s):  
Claudia Maria Hattinger ◽  
Maria Pia Patrizio ◽  
Leonardo Fantoni ◽  
Chiara Casotti ◽  
Chiara Riganti ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
Cure Rate ◽  
Acquired Drug Resistance ◽  
Unselected Patient ◽  
Dismal Prognosis ◽  
Non Coding Rnas ◽  
High Grade Osteosarcoma

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.

scholarly journals SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jian Wu ◽  
Min Zhang ◽  
Omar Faruq ◽  
Eldad Zacksenhaus ◽  
Wenming Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Therapeutic Target ◽  
Biological Activities ◽  
Xenograft Model ◽  
Myeloma Cell ◽  
Soft Agar ◽  
Drug Resistant ◽  
Migration Assay

Abstract Background SMAD1, a central mediator in TGF-β signaling, is involved in a broad range of biological activities including cell growth, apoptosis, development and immune response, and is implicated in diverse type of malignancies. Whether SMAD1 plays an important role in multiple myeloma (MM) pathogenesis and can serve as a therapeutic target are largely unknown. Methods Myeloma cell lines and primary MM samples were used. Cell culture, cytotoxicity and apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, and migration assay, Chromatin immunoprecipitation (Chip), animal xenograft model studies and statistical analysis were applied in this study. Results We demonstrate that SMAD1 is highly expressed in myeloma cells of MM patients with advanced stages or relapsed disease, and is associated with significantly shorter progression-free and overall survivals. Mechanistically, we show that SMAD1 is required for TGFβ-mediated proliferation in MM via an ID1/p21/p27 pathway. TGF-β also enhanced TNFα-Induced protein 8 (TNFAIP8) expression and inhibited apoptosis through SMAD1-mediated induction of NF-κB1. Accordingly, depletion of SMAD1 led to downregulation of NF-κB1 and TNFAIP8, resulting in caspase-8-induced apoptosis. In turn, inhibition of NF-κB1 suppressed SMAD1 and ID1 expression uncovering an autoregulatory loop. Dorsomorphin (DM), a SMAD1 inhibitor, exerted a dose-dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells, and further synergized with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells in vitro and in a myeloma xenograft model. Conclusions This study identifies SMAD1 regulation of NF-κB1/TNFAIP8 and ID1-p21/p27 as critical axes of MM drug resistance and provides a potentially new therapeutic strategy to treat drug resistance MM through targeted inhibition of SMAD1.

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