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Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

ABSTRACT: Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling. Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells. To investigate large scale alterations in gene expression accompanying melphalan resistance, we used the multiple myeloma cell line RPMI8226 and its melphalan-resistant derivative LR5. The stable isotope labeling by amino acids in cell culture (SILAC) approach.

OTHER RELATED OMICS DATASETS IN: PRJNA260009

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Myeloma

SUBMITTER: Animesh Sharma

LAB HEAD: Geir Slupphaug

PROVIDER: PXD001276 | Pride | 2015-05-26

REPOSITORIES: Pride

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Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells.

Zub Kamila Anna KA Sousa Mirta Mittelstedt Leal de MM Sarno Antonio A Sharma Animesh A Demirovic Aida A Rao Shalini S Young Clifford C Aas Per Arne PA Ericsson Ida I Sundan Anders A Jensen Ole Nørregaard ON Slupphaug Geir G

PloS one 20150313 3

Alkylating agents are widely used chemotherapeutics in the treatment of many cancers, including leukemia, lymphoma, multiple myeloma, sarcoma, lung, breast and ovarian cancer. Melphalan is the most commonly used chemotherapeutic agent against multiple myeloma. However, despite a 70-80% initial response rate, virtually all patients eventually relapse due to the emergence of drug-resistant tumour cells. By using global proteomic and transcriptomic profiling on melphalan sensitive and resistant RPM ...[more]

PMID: 25769101

Similar Datasets

Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

2014-09-03 | GSE60970 | GEO

Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

Project description:Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells. The gene expression profiles were measured on 6 batches each of control and melphalan-treated RPMI8226 and RPMI8226-LR5 cells using Illumina Human HT-12 v3 Expression BeadChip (Illumina, San Diego, CA), which enables genome-wide expression analysis (more than 47 000 transcripts) of 24 samples in parallel on a single microarray.

2014-09-03 | E-GEOD-60970 | biostudies-arrayexpress

Metabolic Changes Contribute to Melphalan Resistance in Multiple Myeloma

Project description:Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the U.S. Treatment for eligible patients includes three stages: induction, consolidation with stem cell rescue, and maintenance. High dose therapy with the DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem cell transplant. As a result, melphalan resistance remains a clinical challenge. Here, we use proteometabolomics to examine mechanisms of melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP), acute treatment metabolomics, and immunoblotting analyses have allowed us to further elucidate metabolic processes contributing to melphalan resistance. Proteometabolomics data indicate that both drug resistant cells have higher levels of pentose phosphate pathway metabolites than their naïve counterparts. Interestingly, we also observed cell line specific changes in purine, pyrimidine and glutathione metabolism that are linked to the differences in steady state metabolism of naïve cells and highlight the heterogeneity of melphalan resistance in these models. Because of the diversity of metabolic changes, our data suggest that omics approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the delivery of this therapy.

2020-07-17 | PXD019725 | Pride

Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder

Project description:Increasing evidences indicate diet-induced metabolic disorder could be paternally inherited, but the exact sperm epigenetic carrier remains unclear. Here, in a paternal high-fat diet (HFD) mouse model, we revealed that a highly enriched subset of sperm small RNAs (30-34 nt) that derived from the 5â halves of tRNAs (tsRNAs), exhibit changes in both expression profiles and RNA modifications. Injection of sperm tsRNAs from HFD male but not synthetic tsRNAs lacking RNA modifications, into normal zygotes generated metabolic disorders in the F1 offspring. Injection of HFD sperm tsRNAs derails gene expression in both early embryos and islets of F1 offspring, enriched in metabolic pathways, but unrelated to DNA methylation at CpG-enriched region. Collectively, we uncover sperm tsRNAs as a type of âepigenetic carrierâ that mediate intergenerational inheritance of acquired traits. Mature sperm small-RNA profiles between High-fat-diet (HFD) and Normal-diet (ND) males; Transcriptional profiles of 8-cell embryos and balstocysts that developed from zygotes that injected with sperm RNAs from HFD vs ND males. Transcriptional profiles and RRBS profiles of islets of F1 offsrping that generated from zygotes that injected with sperm RNAs from HFD vs ND males.

2015-12-31 | E-GEOD-75544 | biostudies-arrayexpress

Transcriptome and phosphoproteome analyses of gemcitabine-resistant gallbladder cancer cells provide novel insights into molecular changes occurring during acquired resistance

Project description:Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but unfortunately the effectiveness of any regimen is limited, and recurrence rates are high. Here, we established and characterized two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR) to investigate the molecular mechanisms associated with acquired resistance in vitro. The transcriptome profiling of parental and gemcitabine resistant cells revealed differential expression of multiple protein-coding genes and enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, quantitative phosphotyrosine proteomic analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as Abl, PDGFRA, EphB2 and members of the Src-family that could be novel therapeutic targets against drug resistance in GBC. In line with this, NOZ GemR cells showed increased sensitivity toward the multikinase inhibitor dasatinib compared with parental cells. In conclusion, our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant gallbladder cancer cells, which greatly expands our understanding of the underlying mechanisms of acquired drug-resistance in GBC. Moreover, this new gemcitabine resistant GBC models could be exploited either to study alternative mechanisms of resistance or to explore new therapies for chemotherapy-refractory GBC.

2023-05-03 | PXD036348 | Pride

Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis

Project description:Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis

2023-07-10 | PXD043632 | iProX

Proteomic analysis of centrosome-associated proteins between non-activated non-polarized and activated polarized murine B cells R#1 (R#2 doi: 10.1038/ncomms10969) & R#3

Project description:Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics on purified centrosomes from resting, non-activated non-polarized, and activated polarized mouse B cells, we established a list of proteins differentially associated with the centrosome between resting and polarized states.

2022-12-12 | PXD038725 | Pride

Network-based integration of multi-omics data identifies the determinants of miR-491-5p effects

Project description:The identification of miRNAs’ targets and associated regulatory networks might allow the definition of new strategies using drugs whose association might mimic a given miRNA’s effects. Based on this assumption our group devised a multi-omics approach in an attempt to precisely characterize miRNAs’ effects. We combined the analysis of miR-491-5p direct targets, and effects at the transcriptomic and proteomic levels. We thus constructed an interaction network which enlightened highly connected nodes, being either direct or indirect targets of miR-491-5p effects: the already known EGFR and BCL2L1, but also EP300, CTNNB1 and several small-GTPases. By using different combinations of specific inhibitors of these nodes, we could greatly enhance their respective cytotoxicity and mimic miR-491-5p-induced phenotype. Our methodology thus constitutes an interesting strategy to comprehensively study the effects of a given miRNA. Also, we identified targets for which pharmacological inhibitors are already available for a clinical use, or in clinical trial phases. This study might thus enable innovative therapeutic options for ovarian cancer, which remains the first cause of death from gynecological malignancies in developed countries.

2021-09-09 | PXD022131 | Pride

Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

2022-05-27 | PXD032030 | Pride

Tissue-resident macrophages promote multiple myeloma early dissemination and progression via IL-6 and TNFa

Project description:Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci indicate cycles of tumor growth and dissemination that seed new clusters and drives disease progression. Utilizing an intra-tibial Vk*MYC murine myeloma, we found that CD169 + radiation-resistant, tissue-resident macrophages (MPs) were critical for myeloma early dissemination and disease progression. While depletion of these MPs had no effect on tumor proliferation, it reduced myeloma BM egress and spreading to other bones, which improved overall survival as a single therapy and in combination with BM transplantation. Myeloma dissemination correlated with an increased inflammatory signature in BM MPs, as well as production of IL-6 and TNFα by tumor-associated MPs (TAMs). Exogenous i.v. IL-6 and TNFa could trigger myeloma intravasation in the BM by increasing vascular leakiness in the BM, and by enhancing myeloma motility by reducing CD138 adhesion. Moreover, mice lacking IL-6 had defects in myeloma dissemination as in MP-depleted recipients. While in TNFa or TNFaR deficient mice had defects in MM dissemination, engraftment was also impaired. These effects on myeloma dissemination required production of cytokines in the radiation-resistant compartment, containing these radiation-resistant BM MPs. Taken together, we propose BM egress of myeloma cells is regulated by localized inflammation in foci, driven in part by CD169 + MPs.

2021-06-09 | GSE176385 | GEO

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