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Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer

ABSTRACT: Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal β-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218282 | GEO | 2023/12/31

REPOSITORIES: GEO

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Integrative Omics reveals changes in the cellular landscape of yeast without peroxisomes

Project description:Peroxisomes are organelles that are crucial for cellular metabolism. However, these organelles play also important roles in non-metabolic processes, such as signalling. To uncover the consequences of peroxisome deficiency, we compared two extremes, namely Saccharomyces cerevisiae wild-type and pex3 cells, which lack functional peroxisomes, employing transcriptomics and quantitative proteomics technology. Cells were grown on acetate, a carbon source that involves peroxisomal enzymes of the glyoxylate cycle and does not repress peroxisomal proteins. Transcripts of peroxisomal β-oxidation genes and the corresponding proteins were enhanced in pex3 cells. Peroxisome-deficiency also caused reduced levels of membrane bound peroxins, while the soluble receptors Pex5 and Pex7 were enhanced at the protein level. In addition, we observed alterations in non-peroxisomal transcripts and proteins, especially mitochondrial proteins involved in respiration or import processes. Our results not only reveal the impact of the absence of peroxisomes in yeast, but also represent a rich resource of candidate genes/proteins that are relevant in peroxisome biology.

2024-05-01 | GSE261289 | GEO

Characterization of peroxisome-associated transcriptome

Project description:This is a pioneer genome-wide study of localization of mRNAs to peroxisomes. The findings suggest that translation of a subset of peroxiomal proteins and other cellular metabolic enzymes may be spatially regulated by directing their encoding mRNAs to the surface of peroxisomes. The study provides foundation for more detailed dissection of mechanisms of RNA targeting to subcellular compartments. In this study we performed the genome-wide transcriptome analysis of peroxisome preparations from the mouse liver using microarrays. We demonstrate that RNA is absent inside peroxisomes, however it is associated at their exterior via the noncovalent contacts with the membrane proteins. We detect enrichment of specific sets of transcripts in two preparations of peroxisomes, purified with different degrees of stringency. Importantly, among these were mRNAs encoding bona fide peroxisomal proteins, such as peroxins and peroxisomal matrix enzymes involved in beta-oxidation of fatty acids and bile acid biosynthesis. Two subcellular fractions were obtained from the mouse liver by centrifugation in iodixanol density gradient: 1) Peroxisomal (PX), 2) Mitochondrial/Lysosomal (ML). The membrane-enclosed peroxisomal fraction (PX-IP) was obtained by immuno-precispitation of the PX fraction with the PMP70-specific antibodies. RNA was extracted from each fraction. Additionally, the total cellular RNA was obtained from the whole cell extracts (T). Thus, four RNA sample types were obtained for gene expression analysis: T, ML, PX, PI. Three technical replicates of each sample ware analyzed with Illumina microarrays.

2016-07-29 | E-GEOD-84972 | biostudies-arrayexpress

Peroxisomal retrograde signaling in C. elegans

Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.

2020-12-19 | GSE156318 | GEO

Characterization of peroxisome-associated transcriptome

2016-07-29 | GSE84972 | GEO

Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis

Project description:Peroxisomes play an essential role in the β-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ω-oxidation of fatty acids. The physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). We performed RNA-seq in WT and Ehhadh KO livers, treated with vehicle or L-aminocarnitine (L-AC), an inhibitor of mitochondrial fatty acid oxidation. We show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA β-oxidation is a regulator of hepatic cholesterol biosynthesis.

2021-04-02 | GSE171292 | GEO

Chaperone-mediated autophagy promotes PCa survival during ARPI through selective proteome remodeling

Project description:Defining acute stress response mechanisms that mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with androgen receptor pathway inhibition (ARPI). ARPI causes abrupt environmental changes, subjecting PCa cells to acute metabolic stress. We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC). CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. As mediator of selective protein degradation, CMA orchestrates cellular pathway changes mediating the cellular stress response. Broad-spectrum proteomic analysis identified CMA induced proteome remodeling acutely after ARPI stress. CMA sustained PCa growth and survival during ARPI, promoting metabolic reprogramming through the upregulation mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. The upregulation of CMA promotes PCa cell proliferation after ARPI, and emergence of CRPC in-vivo. CMA inhibition compromised PCa metabolism, leading to ATP depletion and profound anti-proliferative effects on PCa cells, enhanced when combined with ARPI. CMA inhibition prevented in-vivo tumour formation, while also re-sensitizing enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. This study established CMA as an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress to promote PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa.

2023-01-26 | PXD036227 | Pride

Peroxisome function relies on organelle-associated mRNA translation

Project description:Crucial metabolic functions of peroxisomes rely on a variety of peroxisomal membrane proteins (PMPs). While mRNA transcripts of PMPs were shown to be colocalized with peroxisomes, the process by which PMPs efficiently couple translation with targeting to the peroxisomal membrane remained elusive. Here, we combine quantitative electron microscopy with proximity-specific ribosome profiling and reveal that translation of specific PMPs occurs on the surface of peroxisomes in the yeast Saccharomyces cerevisiae. This places peroxisomes alongside chloroplasts, mitochondria, and the endoplasmic reticulum as organelles that use localized translation for ensuring correct insertion of hydrophobic proteins into their membranes. Moreover, the correct targeting of these transcripts to peroxisomes is crucial for peroxisomal and cellular function, emphasizing the importance of localized translation for cellular physiology.

2022-01-12 | GSE113567 | GEO

Evolution Anaerobic peroxisome in Mastigamoeba balamuthi

Project description:Adaptation of eukaryotic cells to anaerobic condition is reflected by deep changes in mitochondrial metabolism and their functional reduction. The most modified types of mitochondria are hydrogenosomes that generate molecular hydrogen with concomitant ATP synthesis and mitosome that completely lost energy metabolism. The reduction of mitochondria is associated with loss of peroxisomes that evolved from ER to compartmentalize pathways generating reactive oxygen species (ROS) and thus prevent cellular oxidative damage. Biogenesis and function of peroxisomes is tightly coupled with mitochondria. They share the fission machinery, pathways of oxidative metabolism, ROS scavenging, and metabolic products. The loss of peroxisomes in anaerobic eukaryotes with reduced mitochondria is thus not unexpected. Surprisingly, we identified peroxisomes in anaerobic, hydrogenosome bearing protist Mastigamoeba balamuthi. Initially, we identified conserved set of peroxisomal proteins peroxins that are required for protein import, peroxisomal growth and division. Key membrane associated peroxins (MbPex3, MbPex11, and MbPex14) were visualized in numerous vesicles that were distinct from hydrogenosomes, ER and Golgi body. Proteomic analysis of cellular fractions and prediction of peroxisomal targeting signals (PTS1/PTS2) allows identification of 51 putative peroxisomal matrix proteins. Expression of selected proteins in Saccharomyces cerevisiae revealed that they are specifically targeted to yeast peroxisomes. Matrix protein includes components of acyl CoA and carbohydrate metabolism, pyrimidine and CoA biosynthesis, whereas neither components of β-oxidation nor catalase were present. In conclusion, we identified new subclass of peroxisomes named “anaerobic” peroxisome that shifts the current paradigm and rises attention to reductive evolution of peroxisomes in anaerobic organisms.

2020-03-04 | PXD014205 | Pride

Transcription profiling of Arabidopsis peroxisomal mdh mutant

Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana; Experimenter phone = 0131 650 5316; Experimenter fax = 0131 650 5392; Experimenter department = Institute of Molecular Plant Sciences; Experimenter institute = University of Edinburgh; Experimenter address = Daniel Rutherford Building University of Edinburgh; Experimenter address = The King's Buildings; Experimenter address = Edinburgh; Experimenter zip/postal_code = EH9 3JH; Experimenter country = UK Experiment Overall Design: 6 samples were used in this experiment

2008-06-13 | E-GEOD-5641 | biostudies-arrayexpress

Peroxisomes are dispensable for normal renal function.

Project description:Peroxisomes are highly abundant in proximal tubules where peroxisomal enzymes have been proposed to play an important role in a variety of metabolic and antioxidant functions. This hypothesis was supported by human genetic studies that identified mutations leading to peroxisomal biogenesis deficiency, resulting in severe multi-organ damage (Zellweger’s spectrum disorders (ZSD)), including renal impairment. However, the role of proximal tubule peroxisomes in renal (patho)physiology remains uninvestigated. We addressed this question in mice with conditional ablation of peroxisomal biogenesis in the renal tubule. Our results demonstrate that renal tubular peroxisomes are dispensable for normal renal function and suggest that renal damage in ZSD patients is of extrarenal origin.

2022-03-02 | GSE179202 | GEO

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