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Dynamic interplay between sortilin and syndecan-1 has a role in the metabolic switch during prostate cancer progression

ABSTRACT: Prostate cancer development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Androgen deprivation therapy (ADT) provides short-term efficacy for patient treatment, but inevitably promotes a castration-resistant phenotype with poor prognosis. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for prostate cancer patients who have poor expected outcomes and/or receive ADT. Here we show that there is a dynamic balance between sortilin and syndecan-1 that reports on different metabolic phenotypes. Sortilin, enhances glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, syndecan-1 interacts with LPL and β3 integrin, to promote lipid metabolism and this process is upregulated in androgen-insensitive cells. We report a hitherto unappreciated molecular mechanism for prostate cancer, which has significance for disease progression and how ADT may promote castration-resistant prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220618 | GEO | 2023/08/21

REPOSITORIES: GEO

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Intraprostatic Androgens and Androgen-Regulated Gene Expression Persist Following Testosterone Suppression

Project description:Introduction: Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer (PCa). The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene-expression. Design: Androgen levels and androgen-regulated gene-expression (by microarray-profiling, qRT-PCR and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the GnRH-antagonist, Acyline, vs. placebo in healthy men. To assess the effects of long-term ADT, gene-expression measurements were evaluated at baseline and after 3, 6 and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized PCa. Results: Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and PSA, were not suppressed after short-term castration, nor after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in PCa samples at each time-point of ADT. Conclusions: Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene-expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing PCa cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment. Keywords: prostate, androgen, Acyline, microarray, immunohistochemistry

2007-10-25 | GSE8466 | GEO

THEM6-mediated lipid remodelling sustains stress resistance in cancer (Part2 : THEM6 KO in 22rv1)

Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. As a consequence, THEM6 loss in CRPC cells significantly alters ER function, preventing lipid-mediated induction of ATF4 and reducing de novo sterol biosynthesis. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.

2021-12-11 | PXD024456 | Pride

THEM6-mediated lipid remodelling sustains stress resistance in cancer (Part3 : THEM6 KO in LNCaP AI)

2021-12-11 | PXD024433 | Pride

THEM6-mediated lipid remodelling sustains stress resistance in cancer (Part1 : AP-MS)

2021-12-11 | PXD024407 | Pride

Expression data from MCRedAL Prostate Tumors

Project description:Prostate tumor cells growth is interconected to androgen signaling. Indeed, the main line of treatment for advanced prostate cancer is focused on inhibiting androgen signaling by either surgical or pharmacological castration (or androgen-ablation, e.g. degarelix). We used microarrays to detail the global programme of gene expression following androgen-deprivation therapy (ADT) and identified distinct classes of up-regulated genes during this process that could contribute to the development of castration resistance.

2021-04-06 | GSE171491 | GEO

Next generation sequencing of advanced non-castrate prostate cancer treated with docetaxel chemotherapy

Project description:Early chemotherapy for advanced/metastatic non-castration resistant prostate cancer (PCa) may improve overall patient survival. We studied the safety, tolerability and early efficacy of up-front docetaxel chemotherapy and androgen deprivation therapy (ADT) versus ADT alone for patients with newly-diagnosed advanced/metastatic PCa. As proof of concept, we undertook in vivo gene expression profiling by next generation RNA sequencing (RNA-Seq). Tumour biposies from 6 patients were taken before and after treatment with combined ADT and docetaxcel for 6 weeks

2014-09-18 | E-GEOD-51005 | biostudies-arrayexpress

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

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

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

2022-10-14 | PXD021405 | Pride

Next generation sequencing of advanced non-castrate prostate cancer treated with docetaxel chemotherapy

2014-09-18 | GSE51005 | GEO

Modeling androgen deprivation therapy-induced prostate cancer dormancy and its clinical implications

Project description:Purpose: Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer (PCa) treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced PCa dormancy remains poorly understood due to the challenge in acquiring clinical dormant PCa cells and the lack of representative models. We, therefore, aimed to develop clinically relevant models that can be used for studying ADT-induced PCa dormancy. Experimental design: Dormant PCa models were established by castrating mice bearing PCa patient-derived xenografts (PDXs) of hormonal naïve or sensitive PCa. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and post-castration (dormant) PDX tissues were subjected to morphological and transcriptome profiling analyses. Results: We established eleven ADT-induced dormant PCa models that closely mimicked the clinical courses of ADT-treated PCa. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in pre-castration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve PCa and clinical outcome in castration-resistant PCa treated with ADT or androgen-receptor pathway inhibitors.

2022-01-11 | GSE193500 | GEO

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