Chronic hypoxia favours adoption to a castration-resistant cell state in prostate cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227811 | GEO | 2023/04/06
REPOSITORIES: GEO
Similar Datasets
Project description:Chronic hypoxia favours adoption to a castration-resistant cell state in prostate cancer
| PRJNA947118 | ENA
Project description:Predicting and treating recurrence in intermediate-risk prostate cancer patients remains a challenge despite having identified genomic instability [1] and hypoxia [2, 3] as risk factors. This underlies challenges in assigning the functional impact of these risk factors to mechanisms promoting prostate cancer progression. Here we show chronic hypoxia (CH), as observed in prostate tumours [4], leads to the adoption of an androgen-independent state in prostate cancer cells. Specifically, CH results in prostate cancer cells adopting transcriptional and metabolic alterations typical of castration-resistant prostate cancer cells. These changes include the increased expression of transmembrane transporters for the methionine cycle and related pathways leading to increased abundance of metabolites and expression of enzymes related to glycolysis. Targeting of the Glucose Transporter 1 (GLUT1) identified a dependency on glycolysis in androgen-independent cells. Overall, we identified a therapeutically targetable weakness in chronic hypoxia and androgen-independent prostate cancer. These findings may offer additional strategies for treatment development against hypoxic prostate cancer.
| S-EPMC10202808 | biostudies-literature
Project description:To examine changes in tyrosine kinase activity in prostate cancer tumors developing resistance to androgen deprivation therapy and to compare these to changes in tyrosine kinase activity occuring in cell lines exposed to oxygen deficiency (hypoxia)
2013-04-15 | E-MTAB-1572 | biostudies-arrayexpress
Project description:Hypoxia inducible factor 1 (HIF1) has been shown to cooperate with the androgen receptor (AR) in activation of oncogenic pathways in prostate cancer (PCa). Here we hypothesized that HIF1 also plays a role in PCa response to androgen deprivation therapy (ADT). Comparison of gene expression profiles of androgen exposed (AE) and androgen deprived (AD) CWR22 PCa xenografts identified 596 upregulated and 748 downregulated genes after ADT. Gene ontology (GO) analysis of the differentially expressed genes showed significant enrichment of the biological processes cell proliferation, cell cycle and metabolism and suggested suppression of these processes after ADT. A set of 80 hypoxia-inducible genes were identified in 22Rv1 and LNCaP cell lines treated with hypoxia and showed considerable overlap (53%) with the downregulated genes. Immunostaining of the hypoxia marker pimonidazole showed no difference between AE- and AD-tumors. Comparison of the differentially expressed genes with lists of 1115 direct AR- and 276 direct HIF1-target genes identified 138 AR- and 40 HIF1-targets that were regulated after ADT, including six shared AR- and HIF1-targets for which downregulation was confirmed with RT-PCR. Most HIF1-targets were downregulated and included in the significant biological processes and the set of hypoxia-inducible genes. The downregulation of HIF1-targets was consistent with decreased HIF1A immunostaining in AD- compared to AE-tumors (p=0.002). A decrease in HIF1A immunostaining after ADT was also demonstrated in a cohort of 35 PCa patients (p<0.001). These data suggest suppressed HIF1-signaling after ADT and a shared role of HIF1 and AR in the regressive phase of PCa after ADT. Prostate cancer xenografts were subjected to adrogen deprivation therapy and analysed with regard to changes in gene expressions. Cell culture experiments were performed to generate prostate cancer specific gene lists associated with hypoxia.
2013-10-02 | E-GEOD-42868 | biostudies-arrayexpress
Project description:The transcription factor GATA2 regulates chemotherapy resistance in prostate cancer. We report a novel GATA2 transcriptional program that has implications for chemotherapy resistance disease and aggressiveness in castration resistant prostate cancer. Examination of the transcriptional network changes induced in human Ch-CRPC cell lines by two shRNA mediated knock down of GATA2 versus random shRNA control
2014-11-04 | E-GEOD-58966 | biostudies-arrayexpress
Project description:Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.
2022-04-06 | PXD021428 | Pride
Project description:Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.
2022-10-14 | PXD021405 | Pride
Project description:Transcription profiling by high throughput sequencing of advanced prostate cancer treated with androgen-deprivation therapy
2025-01-24 | E-GEOD-48403 | ExpressionAtlas
Project description:Background: Constant hypoxia (CH) and intermittent hypoxia (IH) occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s) in D. melanogaster after exposure to severe (1% O2) intermittent or constant hypoxia. Methodology/Principal Findings: Our microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated) in hypoxia tolerance (adult survival) for longer periods (CH-7 days, IH-10 days) under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70) led to a significant increase in adult survival (as compared to controls) of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(2)08717 genes (P-element lines) provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies. Conclusions/Significance: We observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(2)08717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival. Expression profiles were determined by expression arrays in Drosophila melanogaster following acute constant or intermittent hypoxia. Three groups of samples were included in this analysis (3 x control, 3x CH treated and 3 x IH treated samples).
2009-04-30 | E-GEOD-14981 | biostudies-arrayexpress
Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.
2017-08-15 | E-MTAB-4991 | biostudies-arrayexpress