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Glucose Metabolic Remodeling through Phosphoenolpyruvate Carboxykinase Isoform 2 Regulates Prostate Cancer Cell Tumorigenicity

ABSTRACT: Patients with aggressive prostate cancer generally present with poor outcomes. Identifying the factors regulating prostate cancer aggressiveness may open new avenues in therapy. Specifically, information from prostate cancer patient databases revealed that higher phosphoenolpyruvate carboxykinase isoform 2 (PCK2) levels correlate with more aggressive tumors and lower survival rates. Herein, we show that high tumorigenic prostate cancer cell clones express high levels of PCK2. We found that elevated levels of PCK2 are critical for the glucose metabolic remodeling and the maintenance of tumor-initiating cells (TICs) in aggressive prostate cancer. Our data suggest that PCK2 promotes tumorigenicity by lowering acetyl-CoA levels through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76470 | GEO | 2016/01/04

SECONDARY ACCESSION(S): PRJNA307536

REPOSITORIES: GEO

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Glucose Metabolic Remodeling through Phosphoenolpyruvate Carboxykinase Isoform 2 Regulates Prostate Cancer Cell Tumorigenicity

Project description:Patients with aggressive prostate cancer generally present with poor outcomes. Identifying the factors regulating prostate cancer aggressiveness may open new avenues in therapy. Specifically, information from prostate cancer patient databases revealed that higher phosphoenolpyruvate carboxykinase isoform 2 (PCK2) levels correlate with more aggressive tumors and lower survival rates. Herein, we show that high tumorigenic prostate cancer cell clones express high levels of PCK2. We found that elevated levels of PCK2 are critical for the glucose metabolic remodeling and the maintenance of tumor-initiating cells (TICs) in aggressive prostate cancer. Our data suggest that PCK2 promotes tumorigenicity by lowering acetyl-CoA levels through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate cancer. 2 subclones have been isolated from DU145 cells. The epithelial like (EL) clone has a high tumorigenicity ability and enriched tumor initiating cells than mesenchymal like (ML) clone. Genes with differential expression pattern between these two clones were detected by gene micorarray.

2016-01-04 | E-GEOD-76470 | biostudies-arrayexpress

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and glucose-independent tumor cell growth

Project description:Cancer cells must adapt metabolically to survive and proliferate when nutrients are limiting. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell growth. We found that glucose deprivation stimulated the re-wiring of the tricarboxylic acid (TCA) cycle and co-opting early steps of gluconeogenesis to promote cell proliferation under low glucose. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine, which was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. Mitochondrial PEP-carboxykinase (PCK2) was required for this glutamine-dependent metabolic reprogramming. PCK2 expression was dependent on the hypoxia-inducible factors (HIFs), and required to maintain tumor cell proliferation under limiting glucose availability. Elevated PCK2 expression is observed in several human tumor types, and enriched in tumor tissue from non-small cell lung cancer (NSCLC) patients. Our results define a novel role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

2015-10-15 | GSE66556 | GEO

Homo sapiens

Project description:Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) regulates metabolic adaptation and glucose-independent tumor cell growth

| PRJNA277316 | ENA

Homo sapiens

Project description:Glucose Metabolic Remodeling through Phosphoenolpyruvate Carboxykinase Isoform 2 Regulates Prostate Cancer Cell Tumorigenicity

| PRJNA307536 | ENA

Catabolite repression of phosphoenolpyruvate carboxykinase by a zinc finger protein under biotin- and pyruvate carboxylase-deficient conditions in Pichia pastoris

Project description:We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P.pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose ammonium (Bio-) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (∆ROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ∆ROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ∆ROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ∆ROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ∆ROP strain. To our knowledge, ROP is the first example, of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions.

2011-10-14 | GSE32948 | GEO

Catabolite repression of phosphoenolpyruvate carboxykinase by a zinc finger protein under biotin- and pyruvate carboxylase-deficient conditions in Pichia pastoris

2011-10-13 | E-GEOD-32948 | biostudies-arrayexpress

Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Project description:Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally down-regulated protein 8, to target proteins, with yet-unknown consequences. Here we show in mice that neddylation in liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver (either pharmacologically or genetically) reduces gluconeogenic capacity and the hyperglycemic actions of counterregulatory hormones (glucagon, adrenaline and glucocorticoids). Further, people with obesity and type 2 diabetes (compared to people with obesity and normoglycemia) display elevated hepatic neddylation levels that correlate positively with fasting glucose levels. Mechanistically, we determined that fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342 and K387. PCK1 is a key control point for gluconeogenesis regulation that can be post-translationally modified by acetylation and phosphorylation, but to date no modifications are known to affect its gluconeogenic capacity. Of note, we find that mutating the three PCK1 lysines that are neddylated reduces its gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely-tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

2023-10-08 | PXD043054 | Pride

Phosphoenol-pyruvate carboxykinase isoform 2 (PCK2) causes metabolic defects in endothelial cells and angiogenesis.

Project description:Phosphoenol-pyruvate carboxykinase isoform 2 (PCK2) causes metabolic defects in endothelial cells and angiogenesis.

| PRJEB33275 | ENA

T3 and Glucose Increase Expression of Phosphoenolpyruvate Carboxykinase (Pck1) Leading to Increased ß-Cell Proliferation

Project description:T3 and Glucose Increase Expression of Phosphoenolpyruvate Carboxykinase (Pck1) Leading to Increased ß-Cell Proliferation

| PRJNA903166 | ENA

Mitocans target tryptophan metabolism to remove the mimicry of tumour-initiating cells

Project description:Following therapy, tumour-initiating cells (TICs) survive and give rise to second-line tumours. Gene set enrichment analysis of microarray data and microRNA analysis confirmed the validity of spheroid cultures as models of TICs for breast and prostate cancer and mesothelioma cell lines. Pathway analysis revealed increased Trp metabolism in all types of TICs with indoleamine 2,3-dioxygenase (IDO) as the rate-limiting enzyme. TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. Mitocans, represented by vitamin E (VE) analogues, suppressed IDO1 in TICs with functional mitochondrial complex II, a target for the agents. IDO1 expression was regulated via a mechanism involving both transcriptional and post-transcriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work points to Trp metabolism as a novel mechanism of TICs to bypass the immune surveillance and to VE analogues as agents that remove this ‘mimicry’. Total RNA obtained from from breast cancer (MCF7), mesothelioma (IstMes2) and prostate cancer (LNCaP) adherent cell lines was compared to their corresponding sphere cultures

2013-11-01 | E-GEOD-41980 | biostudies-arrayexpress

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