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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE158085 | GEO | 2020/09/17

REPOSITORIES: GEO

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RNA-seq reveals novel cancer-selective and disease subtype-independent mechanistic targets of withaferin A in human breast cancer cells.

Project description:Withaferin A (WA) exhibits cancer chemopreventive efficacy in preclinical models representative of two different subtypes of breast cancer. However, the mechanism(s) underlying breast cancer chemoprevention by WA is not fully elucidated. We performed RNA-seq analyses using a non-tumorigenic mammary epithelial cell line (MCF-10A) and human breast cancer cells (BCC) belonging to the luminal-type (MCF-7), HER2-enriched (SK-BR-3), and basal-like subtype (MDA-MB-231) to identify novel cancer-selective mechanistic targets of WA. The WA-regulated transcriptome was strikingly different between MCF-10A versus BCC. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulation of genes associated with cellular senescence in WA-treated BCC. Consequently, the number of senescence-associated β-galactosidase positive cells was decreased significantly in WA-treated BCC but not in the MCF-10A cells. WA treatment caused upregulation of senescence marker p21 more robustly in BCC than in MCF-10A. Breast cancer prevention by WA in rats was also associated with upregulation of p21 protein expression. The Reactome pathway analyses indicated upregulation of genes associated with cellular response to stress/external stimuli in WA-treated BCC but not in MCF-10A. Two proteins represented in these pathways (HSPA6 and NRF2) were further investigated. While HSPA6 was dispensable for WA-mediated apoptosis and autophagy or inhibition of cell migration, the NRF2 knockout cells were more resistant to apoptosis resulting from WA treatment than control cells. Finally, expression of some glycolysis-related proteins was decreased by WA treatment both in vitro and in vivo. In summary, this study provides novel insights into cancer-selective pathways affected by WA that may contribute to its chemopreventive efficacy in breast cancer.

| S-EPMC7736309 | biostudies-literature

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

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

| PRJNA663908 | ENA

RNA-Seq reveals novel mechanistic targets of withaferin A (WA) in prostate cancer cells

Project description:RNA-Seq reveals novel mechanistic targets of withaferin A (WA) in prostate cancer cells

| PRJNA565770 | ENA

RNA-seq reveals novel mechanistic targets of withaferin A in prostate cancer cells.

Project description:Withaferin A (WA) is a promising phytochemical exhibiting in vitro and in vivo anticancer activities against prostate and other cancers, but the mechanism of its action is not fully understood. In this study, we performed RNA-seq analysis using 22Rv1 human prostate cancer cell line to identify mechanistic targets of WA. Kyoto Encyclopedia of Genes and Genomes pathway analysis of the differentially expressed genes showed most significant enrichment of genes associated with metabolism. These results were validated using LNCaP and 22Rv1 human prostate cancer cells and Hi-Myc transgenic mice as models. The intracellular levels of acetyl-CoA, total free fatty acids and neutral lipids were decreased significantly following WA treatment in both cells, which was accompanied by downregulation of mRNA (confirmed by quantitative reverse transcription-polymerase chain reaction) and protein levels of key fatty acid synthesis enzymes, including ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase and carnitine palmitoyltransferase 1A. Ectopic expression of c-Myc, but not constitutively active Akt, conferred a marked protection against WA-mediated suppression of acetyl-CoA carboxylase 1 and fatty acid synthase protein expression, and clonogenic cell survival. WA was a superior inhibitor of cell proliferation and fatty acid synthesis in comparison with known modulators of fatty acid metabolism including cerulenin and etomoxir. Intraperitoneal WA administration to Hi-Myc transgenic mice (0.1 mg/mouse, three times/week for 5 weeks) also resulted in a significant decrease in circulating levels of total free fatty acids and phospholipids, and expression of ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase and carnitine palmitoyltransferase 1A proteins in the prostate in vivo.

| S-EPMC7351133 | biostudies-literature

RNA-Seq reveals novel mechanistic targets of withaferin A (WA) in prostate cancer cells

Project description:RNA-Seq analysis using WA-treated 22Rv1 human prostate cancer cells revealed upregulation and downregulation of 6993 and 6607 genes, respectively when compared to the vehicle-treated control. The pathways with significantly upregulated gene expression following WA treatment included mitogen-activated protein kinases, focal adhesion, endocytosis, and autophagy as revealed by KEGG and gene ontology analyses. WA treatment also resulted in downregulation of genes associated with metabolic pathways, oxidative phosphorylation, tricarboxylic acid cycle, cell cycle, and base excision repair. This study identifies novel mechanistic targets of WA in prostate cancer.

2019-09-17 | GSE137519 | GEO

Disease Subtype-Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A.

Project description:A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action.Chemopreventive efficacy of WA (4 and 8?mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n?=?14 for control group, n?=?15 for 4?mg/kg group, and n?=?18 for 8?mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n?=?8-12 for control group, n?=?7-11 for 4?mg/kg group, and n?=?8-12 for 8?mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n?=?4-11 for control group and n?=?4-21 for 4?mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided.Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8?mg/kg group was lower by about 68% compared with controls (8?mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells.WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.

| S-EPMC5928779 | biostudies-literature

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

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

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

Small RNA next generation sequencing of miRNAs in MCF7 cells derived mammosphere treated with withaferin A

Project description:In this study, we reporte the altered miRNAs expression in the human breast cancer cell line (MCF7) derived mammosphere in response to withaferin A IC50 concentrations (2 µM)..

2024-07-29 | GSE181099 | GEO

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