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NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells

ABSTRACT: NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells

PROVIDER: PRJNA508536 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8283890_1.fastq.gz	Fastqsanger.gz
	SRR8283890_2.fastq.gz	Fastqsanger.gz
	SRR8283891_1.fastq.gz	Fastqsanger.gz
	SRR8283891_2.fastq.gz	Fastqsanger.gz
	SRR8283892_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells

Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The Androgen receptor (AR) antagonist Enzalutamide is a FDA approved therapy for treatment of late stage prostate cancer patients and is currently under clinical study for early stage prostate cancer treatment. After a short positive response period, patients will develop drug resistance. In this study we used RNA-sequencing and bioinformatics analysis to identify Notch signaling pathway as a deregulated pathway in Enzalutamide-resistant cells. NOTCH2 and c-MYC positively correlated with AR expression in patients' samples mimicking cells with Enzalutamide-resistance. In Enzalutamide-resistant cells, MR49F and C4-2R, we found that cleaved-NOTCH1, HES1 and c-MYC protein expression are significantly elevated indicating an activated NOTCH1 pathway in those cells. In addition, ADAM10 and ADAM17 had a higher expression in Enzalutamide-resistant cells, suggesting a role for S2 cleavage in the increased cleaved NOTCH1 expression. Furthermore, treatment of Enzalutamide-resistant cells with PF-03084014 in combination with Enzalutamide increased cell death, decreased colony formation ability and re-sensitized Enzalutamide-resistant cells to Enzalutamide. Knockdown of NOTCH1 in C4-2R increases Enzalutamide sensitivity by decreasing cell proliferation and increasing cell death. In a 22RV1 xenograft model, PF-03084014 and Enzalutamide induced a decrease in tumor growth through a reduced cell proliferation and increased apoptosis. These results indicate that Notch1 signaling can contribute to Enzalutamide-resistance in Prostate cancer and inhibition of this pathway can re-sensitize resistant cells to Enzalutamide.

2019-04-01 | GSE123379 | GEO

NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells.

Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.

| S-EPMC6544854 | biostudies-literature

Expression data from prostate cancer cell lines C4-2B (enzalutamide sensitive) and C4-2B-MDVR (enzalutamide resistant) cells

Project description:Prostate cancer C4-2B cells were cultured in enzalutamide in a dose-escalation manner. After sixty passages cells were resistant to enzalutamide, with a specific sets of genes been deregulated. We performed global gene expression analysis by cDNA microarrays to identify genes responsible for enzalutamide resistance in C4-2B-MDVR cells. Enzalutamide resistant C4-2B-MDVR cells were selected from C4-2B cells during long time enzalutamide treatment. Genes responsible for enzalutamide resistance were identified using C4-2B vs. C4-2B-MDVR RNA extraction and hybridization on Affymetrix microarrays.

2015-04-09 | E-GEOD-64143 | biostudies-arrayexpress

Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in Castration-Resistant Prostate Cancer

Project description:Illumina gene array analyses of prostate cancer cell lines that had acquired resistance to Enzalutamide (MDV3100). mRNA analyses of four cell lines (CWR-R1, LAPC-4, LNCaP, and VCAP) cells that were either untreated, treated for 48hrs with Enz (short-term), or continuously grown in Enzalutamide for >6 months.

2016-02-24 | E-GEOD-78201 | biostudies-arrayexpress

Expression data from prostate cancer cell lines C4-2B (enzalutamide sensitive) and C4-2B-MDVR (enzalutamide resistant) cells

2015-04-09 | GSE64143 | GEO

NOTCH dimerization contributes to maintenance of intestinal homeostasis

Project description:NOTCH dimerization contributes to maintenance of intestinal homeostasis

| PRJNA1091961 | ENA

High-throughput profiling of mRNA from parental and Enzalutamide resistant C4-2b prostate cancer cell lines

Project description:We established an enzalutamide-resistant C4-2b prostate cell line that has an active androgen receptor by maintaining the C4-2b cell line in serially increasing concentrations of enzalutamide. Among the CRPC cell lines, we selected the C4-2b cell line because it is known to have AR variants, and we desired to identify enzymes with the ability to regulate the activity of AR variants as well as the wild type AR. After 2 months, we acquired resistant cells in even 10 uM enzalutamide. After validation of enzalutamide-resistant character, we analyzed global changes in mRNA expression by using quantitative mRNA-sequencing analysis.

2020-02-01 | GSE110802 | GEO

Genome-wide analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells

Project description:Analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells. The hypothesis tested in the present study was that enzalutamide influences the expression of genes that are involved in important bioprocesses in prostate cance rcells, including DNA damage response genes and this effect may synergize with poly(ADP-ribose) polymerase inhibitor olaparib in cytotoxicity to prstate cancer cells. prostate cancer cells were pretreated with enzalutamide or vehicle control DMSO for 24 h, followed by treatment with enzalutamide, olaparib, enzalutamide+olaparib, or vehicle control DMSO for 48 h. Gene expression in enzalutamide+olaparib-treated cells was compared with taht in vehicle control- and single agent-treated cells.

2016-07-03 | E-GEOD-69249 | biostudies-arrayexpress

Molecular determinants for enzalutamide-induced transcription in prostate cancer

Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 functions in directing AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.

2019-09-03 | GSE125014 | GEO

Gene expression analysis of enzalutamide resistant MDA PCa 2b prostate cancer cells

Project description:MDA PCa 2b is an androgen-responsive, AR-positive prostate cancer cell line. Here, we report the generation of an Enzalutamide-resistant derivative, MDA PCa 2b-EnzaR. Gene expression of MDA PCa 2b-EnzaR compared to its parental counterpart were assessed by short-read RNA sequencing.

2024-09-26 | GSE254612 | GEO

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