Homo sapiens
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PROVIDER: PRJNA240808 | ENA |
REPOSITORIES: ENA
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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.
2015-08-02 | GSE55728 | GEO
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
Project description:Withaferin A (WA) is a lactone extracted from Withania somnifera commonly known as Ashwagandha. WA has several therapeutic benefits. The current study was aimed to identify biomarkers that could be targeted by WA in prostate cancer (PCA) cells. We have used SILAC approach to identify WA-regulated proteins at 4 h and 24 time points in three PCA cell lines such as LNCaP, 22Rv1 and DU-145. Ontology prediction suggested that WA treatment can upregulate stress-responsive pathways and shutdown translation and cell metabolism to conserve energy. The cytoprotective stress granule (SG) protein G3BP1 showed upregulation in all the three tested cell lines in response to WA treatment, and subsequently, SGs formed at a higher rate in the WA treated cells. Knockdown (KD) of G3BP1 blocked WA-induced SG formation and reduced the cell survival. We speculate that the activation of G3BP1 and the formation of SGs might constitute a mechanism by which PCA cells induce cell protection after WA- treatment. Knock down of SG proteins such as G3BP1 could help to evade the cytoprotective effects of WA and to assist in the sensitization of cells.
2021-07-21 | PXD016759 | Pride
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
Project description:Withaferin A isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to concentrations of Withaferin A (WA) which can be detected systemically in in vivo experiments. Whereas WA revealed attenuation of multiple cancer hallmarks the withanolide analogue Withanone (WN), did not exert any of the described effects in these cells at comparable concentrations. Pathway enrichment analysis identified that WA targeted relevant cancer programs related to cell death, cell cycle and proliferation, which could functionally be validated flow cytometrically and by real-time proliferation xCELLigence assay. With respect to cell motility, invasion and metastasis processes, WA was found to strongly decrease MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This is further supported by gene expression changes which demonstrate increased expression of a validated breast cancer metastasis suppressor gene (BRMS1) and concomitant decreased expression of extracellular matrix-degrading proteases (PLAU, PLAT, ADAM8), cell adhesion molecules (integrins, laminins) as well as pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R). Subsequent in silico network analysis listed key node transcription factors regulating these processes (p53, E2F1, CDKN2A, NRF2) and revealed the role of chromatin modifying enzymes (p300, JARID1B) as central master switches, linking multiple anticancer activities of WA. Furthermore, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking in account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy resistant triple negative breast cancer, WA based therapeutic strategies hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer. Total RNA from 2 different cell lines treated with WA, are compared to their untreated states
2014-04-01 | E-GEOD-53049 | biostudies-arrayexpress
Project description:Withaferin A isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to concentrations of Withaferin A (WA) which can be detected systemically in in vivo experiments. Whereas WA revealed attenuation of multiple cancer hallmarks the withanolide analogue Withanone (WN), did not exert any of the described effects in these cells at comparable concentrations. Pathway enrichment analysis identified that WA targeted relevant cancer programs related to cell death, cell cycle and proliferation, which could functionally be validated flow cytometrically and by real-time proliferation xCELLigence assay. With respect to cell motility, invasion and metastasis processes, WA was found to strongly decrease MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This is further supported by gene expression changes which demonstrate increased expression of a validated breast cancer metastasis suppressor gene (BRMS1) and concomitant decreased expression of extracellular matrix-degrading proteases (PLAU, PLAT, ADAM8), cell adhesion molecules (integrins, laminins) as well as pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R). Subsequent in silico network analysis listed key node transcription factors regulating these processes (p53, E2F1, CDKN2A, NRF2) and revealed the role of chromatin modifying enzymes (p300, JARID1B) as central master switches, linking multiple anticancer activities of WA. Furthermore, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking in account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy resistant triple negative breast cancer, WA based therapeutic strategies hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer.
2014-04-01 | GSE53049 | GEO
Project description:High-risk neuroblastoma is a devastating malignancy with few therapeutic options. We identify withaferin A (WA) as a natural ferroptosis inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA targets and inactivates glutathione peroxidase 4, as well as increases intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which both independently result in ferroptosis. This double-edged mechanism results in a high efficacy of WA compared to etoposide in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing neuroblastoma xenografts growth and relapse rate. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced targeting to the tumor site. Collectively, our data propose a novel therapeutic strategy to kill cancer cells by ferroptosis. High-risk neuroblastoma is a devastating malignancy with few therapeutic options. We identify withaferin A (WA) as a natural ferroptosis inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA targets and inactivates glutathione peroxidase 4, as well as increases intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which both independently result in ferroptosis. This double-edged mechanism results in a high efficacy of WA compared to etoposide in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing neuroblastoma xenografts growth and relapse rate. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced targeting to the tumor site. Collectively, our data propose a novel therapeutic strategy to kill cancer cells by ferroptosis.
2018-05-01 | GSE112384 | GEO
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
Project description:Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a subcytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2’- deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/ progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.
2017-04-06 | GSE97420 | GEO
Project description:Withaferin A (WA) is a major bioactive compound isolated from the medicinal plant Withania somnifera Dunal, also known as ‘‘Ashwagandha’’. A number of published reports suggest various uses for WA including its function as an anti-inflammatory and anti-angiogenic drug molecule. The effects of WA at the molecular level in a cellular environment are not well understood. Knowledge of the molecular mechanism of action of WA could enhance its therapeutic value and may reveal novel pathways it may modulate.
2015-11-10 | PXD003032 | Pride