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The androgen receptor coordinates biosynthesis and proliferation in prostate cancer

ABSTRACT: The androgen receptor (AR) is the major therapeutic target in prostate cancer, although the important targets of the AR have remained obscure. Here we report a detailed genomic profile of AR signalling and find that the AR directly regulates glycolysis, anabolic metabolism and cell cycle regulators in prostate cancer. This coordinated transcriptional program promotes cancer cell proliferation and enhances the macromolecular synthesis needed to produce daughter cells. Clinical gene expression profiles and mechanistic studies highlight the importance of CAMKK2, an AR target which regulates both cell proliferation and metabolism. Thus our genomics study identifies a direct link between AR signalling and aerobic glycolysis (the Warburg effect), providing a new perspective on the oncogenic function of the AR in prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE28126 | GEO | 2011/03/24

SECONDARY ACCESSION(S): PRJNA139851

REPOSITORIES: GEO

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The androgen receptor coordinates biosynthesis and proliferation in prostate cancer

Project description:The androgen receptor (AR) is the major therapeutic target in prostate cancer, although the important targets of the AR have remained obscure. Here we report a detailed genomic profile of AR signalling and find that the AR directly regulates glycolysis, anabolic metabolism and cell cycle regulators in prostate cancer. This coordinated transcriptional program promotes cancer cell proliferation and enhances the macromolecular synthesis needed to produce daughter cells. Clinical gene expression profiles and mechanistic studies highlight the importance of CAMKK2, an AR target which regulates both cell proliferation and metabolism. Thus our genomics study identifies a direct link between AR signalling and aerobic glycolysis (the Warburg effect), providing a new perspective on the oncogenic function of the AR in prostate cancer. 8 Samples: Chromatin IP using AR and PolII in stimulated and unstimulated LNCaP and VCaP cells.

2011-03-23 | E-GEOD-28126 | biostudies-arrayexpress

Starving advanced prostate cancer cells by pharmacological gluose deprivation with a resveratrol trimer trans-Gnetin H [TGH]

Project description:Prostate cancer is a unique disease from a metabolic perspective. Early stage localized prostate cancer does not typically display increased aerobic glycolysis (the Warburg effect), as seen in other malignancies. However, increasing evidence suggests that advanced prostate cancer exhibits the Warburg effect and displays high glucose uptake. We describe here that trans-gnetin H (TGH), a naturally-occurring resveratrol trimer extracted from Paeonia suffruticosa, displays significant anti-cancer effects in advanced prostate cancer cells in vitro. TGH perturbs energy metabolism by blocking the availability of glucose, inducing unfolded protein response (UPR) and C-MYC pathway downregulation in PC-3 cells. Our studies demonstrate the feasibility of targeting aerobic glucose metabolism in advanced prostate cancer and identify TGH as a potential therapeutic candidate.

2023-10-01 | GSE240103 | GEO

Starving advanced prostate cancer cells by pharmacological gluose deprivation with a resveratrol trimer trans-Gnetin H [PDX]

Project description:Prostate cancer is a unique disease from a metabolic perspective. Early stage localized prostate cancer does not typically display increased aerobic glycolysis (the Warburg effect), as seen in other malignancies. However, increasing evidence suggests that advanced prostate cancer exhibits the Warburg effect and displays high glucose uptake. We describe here that trans-gnetin H (TGH), a naturally-occurring resveratrol trimer extracted from Paeonia suffruticosa, displays significant anti-cancer effects in advanced prostate cancer cells xenografted PC-3 cells in vivo.TGH perturbs energy metabolism by blocking the availability of glucose and inducing profound metabolic and transcriptomic changes in prostate cancer cells as demonstrated by RNA-seq. C-MYC, a known driver oncogene in prostate cancer, is downregulated in TGH-treated cells. Our studies demonstrate the feasibility of targeting aerobic glucose metabolism in advanced prostate cancer and identify TGH as a potential therapeutic candidate.

2023-10-01 | GSE240101 | GEO

ATGL deletion in castration-resistant prostate cancer cell line

Project description:Lipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered on the roles of de novo lipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Analysis of patient-derived phosphoproteomics data identified adipose triglyceride lipase (ATGL), a rate-limiting enzyme in the breakdown of triglycerides and previously suspected tumor suppressor, as a target of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-AMP-dependent protein kinase (AMPK) signaling that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL by CAMKK2-AMPK signaling increased ATGL’s lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and imaging mass spectrometry demonstrated ATGL’s profound regulation of prostate cancer lipid metabolism in vitro and in vivo, remodeling membrane composition. Targeting ATGL using molecular, genetic, and/or pharmacological approaches impaired the growth of human and murine prostate cancer cells in culture and xenograft mouse models of CRPC as well as organoid models. The efficacy of ATGL inhibition occurs in a glucose concentration-dependent manner. Accordingly, pharmacological inhibition or depletion of ATGL induced metabolic plasticity with a shift towards glycolysis, which could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as a potential therapeutic target for the treatment of CRPC and provide insights for future combination therapies.

2023-11-22 | GSE243159 | GEO

The early effects of rapid androgen deprivation on human prostate cancer

Project description:The androgen receptor (AR) is the dominant growth factor in prostate cancer. Understanding how it regulates the human transcriptome is of paramount importance. The early effects of castration on human prostate cancer have not previously been studied. In this study 27 patients were medically castrated with degarelix seven days before radical prostatectomy. Resected tumour was compared with matched controlled untreated prostate cancer tissue by means of mass spectrometry, immunohistochemistry and gene expression array (validated by RT-PCR). All patients had castrate levels of serum androgen with reduced levels of intra-prostatic androgen at prostatectomy. Differential expression of known androgen regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5) was observed. We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of AMACR expression and three other genes (FAM129A, RAB27A and KIAA0101) was confirmed. Up-regulation of oestrogen receptor alpha (ESR1) expression was observed in malignant epithelia. This was associated with differential expression of ESR1 regulated genes and correlated with proliferation (Ki67 expression).

2015-10-16 | GSE72920 | GEO

Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer (PART 2)

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

Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer (PART 1)

2022-04-06 | PXD021428 | Pride

The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

Project description:Aberrant activation of the androgen receptor (AR) plays a key role in the progression of prostate cancer. Current strategies to ablate AR signalling are circumvented when castration resistant prostate cancer (CRPC) emerges. Cyclin dependent kinase 7 (CDK7) is necessary for transcription and regulates cell cycle progression, two processes that are commonly deregulated in CRPC. Emerging evidence also suggests a pivotal role for CDK7 in AR-driven transcription, providing a rationale for targeting it in prostate cancer. CT7001, an orally bioavailable compound, was used to achieve pharmacological inhibition of CDK7. CT7001 preferentially engaged with CDK7, resulting in suppression of proliferation, cell cycle arrest, and induction of apoptosis in prostate cancer cell lines. Additionally, CT7001 interfered with transcription mediated by full-length AR as well as constitutively active AR splice variants. Oral administration of CT7001 alone effectively repressed growth in CRPC xenografts, while co-administration with enzalutamide resulted in considerably greater growth inhibition. Transcriptome analysis of treated xenografts affirmed the additive relationship between CT7001 and enzalutamide, both of which targeted pathways involved in AR signalling and cell cycle control.

2023-04-20 | GSE198488 | GEO

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Project description:Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an AR-regulated gene that is upregulated in prostate cancer. Knockdown of 6PGD impairs growth and elicits death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using 2 specific inhibitors, physcion and S3. Both compounds exhibited substantial anti-cancer activity in multiple models of prostate cancer, including aggressive models of castration-resistant disease that are resistant to contemporary therapy. Mechanistically, 6PGD inhibits AMPK signalling, resulting in increased activity of the anabolic pathways regulated by ACC1 and mTOR. Importantly, the ability of S3 to inhibit prostate cancer growth was recapitulated in prospectively collected tumours using a patient-derived explant (PDE) system. Interestingly, inhibition of 6PGD decreases the expression and activity of AR in both cell lines and PDEs, revealing a novel positive feedback loop between these factors. Supporting the biological relevance of this feedback loop, co-targeting of AR and 6PGD was more effective than targeting either factor alone. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

2020-10-01 | GSE152254 | GEO

Regulation of lipid homeostasis in treatment-resistant prostate cancer

Project description:Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we performed a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicated an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineated a subset of proteins consistently associated with ARI resistance.

2020-05-26 | PXD016836 | Pride

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