Dihydroartemisinin inhibits the proliferation of multiple myeloma cancer stem cells via disturbing nuclear lamina and chromatin architecture
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ABSTRACT:
PROVIDER: PRJNA667951 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12790114_1.fastq.gz | Fastqsanger.gz | |||
| SRR12790114_2.fastq.gz | Fastqsanger.gz | |||
| SRR12790115_1.fastq.gz | Fastqsanger.gz | |||
| SRR12790115_2.fastq.gz | Fastqsanger.gz | |||
| SRR12790116_1.fastq.gz | Fastqsanger.gz |
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Project description:We establish a method to reprogram bulk multiple myeloma (MM) cancer cells into MM cancer stem cells (MMSCs) via heterochromatin modulation, which allows us to obtain sufficient functional MMSCs in an efficient manner. Characterization of these induced MMSCs demonstrates that the reprogrammed MMSCs possess the properties of cancer stem cells both phenotypically and functionally. To leverage this model therapeutically, we screened a panel of compounds, and identified dihydroartemisinin (DHA) as a potent anti-MMSCs drug both in vitro and in vivo. DHA induces anti-proliferation effects on MMSCs via nuclear lamina perturbation and chromatin structure alteration. Hi-C analysis reveals that DHA modulates chromatin architecture mainly at the compartmental level and TADs (topologically associating domains) level. The potent anti-MMSCs efficacy and the novel molecular insights establish the therapeutic rationale for DHA in overcoming therapy resistance caused by cancer stem cells.
2023-09-09 | GSE159209 | GEO
Project description:Dihydroartemisinin inhibits the proliferation of multiple myeloma cancer stem cells via disturbing nuclear lamina and chromatin architecture
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Project description:A cDNA microarray composed of 9306 uniEST probes was constructed andapplied to detect the gene expression profile of protoscoleces of E. granulosus treated with dihydroartemisinin in vitro, respectively. Compared with the untreated protoscoleces, 752 genes were up-regulated and 269 genes were down-regulated in protoscoleces treated with dihydroartemisinin. The differential expression genes in protoscoleces induced by dihydroartemisinin were clustered into molecular metabolic process, cell development and differentiation, anatomical structure morphogenesis and formation, and were enriched in calcium signaling pathway, protein processing in endoplasmic reticulum (ER), molecular metabolism and synthesis, Wnt signaling pathway, MAPK signaling pathway, TGF-beta signaling pathway.
2021-09-29 | GSE184908 | GEO
Project description:Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression, is the expansion of regulatory T-cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type-1 interferon (IFN). Blocking IFNAR1 (interferon alpha and beta receptor 1) on Tregs significantly decreases both, myeloma-associated Treg immunosupporessive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of multiple myeloma patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type-1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1 knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type-1 IFN signaling represents a potential strategy to target immunosuppressive Trage function in MM.
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Project description:Control of malaria is threatened by emerging parasite resistance to artemisinin drug (ART) therapies. The molecular details of how Plasmodium malaria parasites response to ART and how this relates to resistance is not clear. To determine how parasites respond to ART by altering gene expression, we performed a transcriptomic study of dihydroartemisinin (DHA) response in P. falciparum K1 strain and in P. berghei ANKA strain. Microarray data from DHA-treated P. falciparum trophozoite stage parasites were compared with data from other ART treatments. Genes with consistent changes in expression were identified, which includes notably down-regulation of cytosolic ribosomal protein genes. RNA-seq data revealed a similar pattern of transcriptomic change, although the pattern was much clearer in that more than one-third of P. falciparum trophozoite genes are differentially expressed with greater statistical support for down-regulation of ribosomal protein genes. The poor overlap of differentially-expressed genes between microarray and RNA-seq and less-well defined patterns for the former suggests that the accuracy of microarray is limited by technological bias. The trophozoite response to DHA is overall âring-likeâ and less âtrophozoite-likeâ, which is consistent with previous findings that Plasmodium can enter a quiescent ring-like state to resist ART. RNA-seq data from DHA-treated P. falciparum rings reveal a more muted response, although there is considerable overlap of differentially expressed genes with DHA-treated trophozoites. In contrast, P. falciparum schizonts are unresponsive to DHA, suggesting that the protective response acts mainly to arrest parasite development through the G2/M checkpoint. The transcriptional response of P. berghei to DHA treatment in vivo in infected mice is strikingly similar to the P. falciparum in vitro ring and trophozoite responses, in which ribosomal protein genes are notably down-regulated. These results suggest Plasmodium species respond to DHA in the same way. This knowledge could be applied to outwit the parasite to deliver more effective artemisinin therapies, and maybe hinder the development of drug resistance. Two condition drug-treatment experiment, Dihydroartemisinin vs. Vehicle control treatment with matched reference untreated controls. Biological replicates: 5 independently grown and harvested experimental culture replicates. One replicate of treatment/reference time-point per array.
2015-10-15 | E-GEOD-61536 | biostudies-arrayexpress
Project description:The objective of this study was to determine whether Dihydroartemisinin (DHA), a drug highly effective in treating malaria infection with good safety, could be repurposed for the treatment of skin fibrosis in systemic sclerosis (SSc). mRNA-seq of primary human fibroblast cultures from healthy donors treated with DHA or vehicle were performed. By KEGG and Reactome analysis, we identified autophagy was one of the most significantly enriched terms.
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Project description:MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation
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Project description:The combination of bortezomib and dexamethasone should become the reference induction treatment for multiple myeloma patients younger than 65 years. Pharmacogenomic profiles of genes involved in response to treatment may help to understand resistance. We performed gene expression profiling in 9 myeloma cell lines, incubated or not with bortezomib and dexamethasone for 6 hours. Supervised analysis identified significantly up regulated genes involved in stress responses. We focused on REDD1 a gene known to be rapidly induced by a wide variety of stress conditions and DNA damages. REDD1 expression was early and highly induced after bortezomib exposure. REDD1 induction was associated with the dephosphorylation of P70 S6 ribosomal kinase (P70S6K), a key substrate of mTOR. These effects were dependent upon cell line. REDD1 was overexpressed within two hours in bortezomib resistant cell lines in association with a cell size decrease. In sensitive cell lines, neither REDD1 induction nor morphological changes occurred. RNA interference mediated inhibition of REDD1 induction abrogates P70S6K dephosphorylation, early transitory cell size reduction and enhances sensitivity to bortezomib - dexamethasone. Our results suggest that mTOR regulation could be a resistance mechanism mediated by REDD1 expression in myeloma cells. Nine cell lines of multiple myeloma studied, incubated or not with bortezomib and dexamethasone, examined with spotted cDNA nylon membrane. Cell line and Code : JJN3 = Vel_1x; L363 = Vel_2x; LP1 = Vel_3x; MDN = Vel_4x; NCI = Vel_5x; RPMI = Vel_6x; SBN = Vel_7x; U266 = Vel_8x; XG1 = Vel_9x.
2010-02-14 | E-GEOD-11866 | biostudies-arrayexpress
Project description:The nuclear lamina is a proteinaceous network of filaments that provide both structural and gene regulatory functions by tethering proteins and large domains of DNA, so-called lamin associated domains (LADs), to the periphery of the nucleus. LADs are a large fraction of the mammalian genome that are repressed, in part, by their association to the nuclear periphery. The genesis and maintenance of LADs is poorly understood as are the proteins that participate in these functions. In an effort to identify proteins that reside at the nuclear periphery and potentially interact with LADs, we have taken a two-pronged approach. First, we have undertaken an interactome analysis of the inner nuclear membrane bound LAP2β to further characterize the nuclear lamina proteome. To accomplish this, we have leveraged the BioID system, which previously has been successfully used to characterize the nuclear lamina proteome. Second, we have established a system to identify proteins that bind to LADs by developing a chromatin directed BioID system. We combined the BioID system with the m6A-tracer system which binds to LADs in live cells to identify LAD proximal and nuclear lamina proteins. In combining these datasets, we have further characterized the protein network at the nuclear lamina as well as identified putative LAD proximal proteins. Our analysis identifies many heterochromatin related proteins related to H3K9 methylation processes as well as many proteins related to cell cycle regulation identifying important proteins essential for LAD function.
2021-03-09 | PXD012943 | Pride