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RNA sequencing reveals that withaferin A reduces overexpression of Bruton's tyrosine kinase in glucocorticoid resistant multiple myeloma cells

ABSTRACT: RNA sequencing reveals that withaferin A reduces overexpression of Bruton's tyrosine kinase in glucocorticoid resistant multiple myeloma cells

PROVIDER: PRJNA681920 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13178282.fastq.gz	Fastqsanger.gz
	SRR13178283.fastq.gz	Fastqsanger.gz
	SRR13178284.fastq.gz	Fastqsanger.gz
	SRR13178285.fastq.gz	Fastqsanger.gz
	SRR13178286.fastq.gz	Fastqsanger.gz

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Similar Datasets

RNA sequencing reveals that withaferin A reduces overexpression of Bruton's tyrosine kinase in glucocorticoid resistant multiple myeloma cells

Project description:Multiple myeloma (MM) is an incurable hematological malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to multiple existing anti-cancer drugs. Often, this therapy resistance is associated with constitutive activation of Bruton tyrosine kinase (BTK) dependent B-cell receptor (BCR) signaling. Novel kinase inhibitors covalently targeting BCR signaling, including the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical Withaferin A (WA), have therefore gained pharmaceutical interest. Remarkably, glucocorticoid (GC)-resistant MM cells overexpressing BTK are more sensitive to WA then to IBR. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. Our results demonstrate that WA treatment triggers dual inhibition of BCR signaling by transcriptional downregulation and covalent cysteine-dependent kinase inhibition of BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal imaging microscopy. Altogether, we show that covalent BCR-BTK kinase inhibition by WA represents an attractive strategy to treat GC-resistant MM.

2021-03-31 | GSE162475 | GEO

Covalent Cysteine Targeting of Bruton's Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells.

Project description:Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells' uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA's promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM.

| S-EPMC8037275 | biostudies-literature

Crosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells

Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.

2023-10-24 | PXD043635 | Pride

Glucocorticoid-resistant B-cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

Project description:Glucocorticoid-resistant B-cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

| PRJEB31697 | ENA

A natural plant derived compound, Withaferin A exploits the stress pathway to induce antitumor immunity

Project description:Analysis of the global effect of plant derived compound Withaferin A on gene expression in rat her-2/neu expressing murine cancer cells at an early time point of 6hrs post treatment. Pathway analyses were performed to determine which metabolic pathways were significantly affected by the Withaferin A.

2014-12-31 | GSE43374 | GEO

Proteomic characterization of Withaferin A-targeted protein networks for the treatment of monoclonal myeloma gammopathies

Project description:Withaferin A (WA), a natural steroid lactone from the plant Withania Somnifera, has been used for many years in traditional Ayurveda medicine to treat inflammation-related conditions, such as ulcers and rheumatism. Today, WA is most often studied because of its antitumor properties. Although many in vitro and in vivo studies have been performed, the identification of Withaferin A protein targets and of its mechanism of antitumor action remains incomplete. Here, we used quantitative chemoproteomics and differential protein expression analysis to characterize the WA antitumor effects on a multiple myeloma cell model. Identified relevant targets were further validated by Ingenuity Pathway Analysis (IPA) and Western Blot. Canonical pathway analysis revealed targeting of the ubiquitination pathway as a main strategy for WA-induced cell death. Further data suggested that WA targets protein networks that are specific for monoclonal gammopathy of undetermined significance (MGUS) and other closely related disorders, such as multiple myeloma (MM) and Waldenström macroglobulinemia (WM). Moreover, 16 of 20 proteins influenced by WA potentially counteract disease progression, suggesting WA can be used as an effective treatment for MGUS and other closely related disorders.

2018-02-23 | PXD006528 | Pride

Withaferin A (WA) causes cell death in prostate cells.

Project description:Withaferin A (WA), a major chemical component of an Indian herb Withania somnifera, induces cell death (apoptosis/necrosis) in a variety of tumor cells, but its molecular mechanism remains elusive. We report that WA induces cell death selectively in high-grade prostate (PC-3 and DU-145) and tongue (SAS) cancer cells but not in normal human fibroblast (TIG-1) and low-grade prostate cancer (LNCaP) cells. To identify genes whose expression levels were up- or down-regulated in prostate cancer cells following WA treatment, we examined the transcriptome profiles of mRNA prepared from TIG-1, LNCaP, PC-3 and DU-145 cells using Agilent’s Whole Human Genome Microarray.

2015-08-02 | E-GEOD-55728 | biostudies-arrayexpress

Novel cancer-selective and disease subtype-independent mechanistic targets of withaferin A in human breast cancer cells

Project description:We report differential gene expression changes by withaferin A in breast cancer cells versus a normal mammary epithelial cell line.

2020-09-17 | GSE158085 | GEO

Exploiting crosstalk between glucocorticoid and mineralocorticoid receptors enhances glucocorticoid-induced killing of multiple myeloma cells

Project description:Long-term glucocorticoid treatment in multiple myeloma is hampered by deleterious side effects. Glucocorticoids bind to the glucocorticoid receptor (GR), which is a crucial drug target because its activation triggers myeloma cell death. The mineralocorticoid receptor (MR) is a closely related nuclear receptor but its impact on glucocorticoid responsiveness in myeloma is unknown. Here we reveal a functional crosstalk between GR and MR that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone enhances Dex-induced cell killing in (primary) myeloma cells. The crosstalk is further evidenced by an endogenous interaction between GR and MR in myeloma cells that is ligand-inducible and by a distinctive gene expression profile. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.

2023-08-23 | GSE200313 | GEO

Small RNA next genration sequencing of miRNAs in Withaferin A treated MDA-MB-231 cells.

Project description:In this study, we reporte the altered miRNAs expression in the human triple negative breast cancer cell line (MDA-MB-231) in response to withaferin A at IC50 (2 µM) concentration.

2023-01-25 | GSE183395 | GEO

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