Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism.

ABSTRACT:

Background

Succinate dehydrogenase (SDH) is a mitochondrial metabolic enzyme complex involved in both the electron transport chain and the citric acid cycle. SDH mutations resulting in enzymatic dysfunction have been found to be a predisposing factor in various hereditary cancers. Therefore, SDH has been implicated as a tumor suppressor.

Results

We identified that dysregulation of SDH components also occurs in serous ovarian cancer, particularly the SDH subunit SDHB. Targeted knockdown of Sdhb in mouse ovarian cancer cells resulted in enhanced proliferation and an epithelial-to-mesenchymal transition (EMT). Bioinformatics analysis revealed that decreased SDHB expression leads to a transcriptional upregulation of genes involved in metabolic networks affecting histone methylation. We confirmed that Sdhb knockdown leads to a hypermethylated epigenome that is sufficient to promote EMT. Metabolically, the loss of Sdhb resulted in reprogrammed carbon source utilization and mitochondrial dysfunction. This altered metabolic state of Sdhb knockdown cells rendered them hypersensitive to energy stress.

Conclusions

These data illustrate how SDH dysfunction alters the epigenetic and metabolic landscape in ovarian cancer. By analyzing the involvement of this enzyme in transcriptional and metabolic networks, we find a metabolic Achilles' heel that can be exploited therapeutically. Analyses of this type provide an understanding how specific perturbations in cancer metabolism may lead to novel anticancer strategies.

SUBMITTER: Aspuria PP

PROVIDER: S-EPMC4322794 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial-mesenchymal transition interlinked with reprogrammed metabolism.

Project description: Not available

| S-EPMC9719259 | biostudies-literature

The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation.

Project description:Colorectal cancer (CRC) stands as the third most significant contributor to cancer-related mortality worldwide. A major underlying reason is that the detection of CRC usually occurs at an advanced metastatic stage, rendering therapies ineffective. In the progression from the in situ neoplasia stage to the advanced metastatic stage, a critical molecular mechanism involved is the epithelial-to-mesenchymal transition (EMT). This intricate transformation consists of a series of molecular changes, ultimately leading the epithelial cell to relinquish its features and acquire mesenchymal and stem-like cell characteristics. The EMT regulation involves several factors, such as transcription factors, cytokines, micro RNAs and long noncoding RNAs. Nevertheless, recent studies have illuminated an emerging link between metabolic alterations and EMT in various types of cancers, including colorectal cancers. In this review, we delved into the pivotal role played by EMT during CRC progression, with a focus on highlighting the relationship between the alterations of the tricarboxylic acid cycle, specifically those involving the succinate dehydrogenase enzyme, and the activation of the EMT program. In fact, emerging evidence supports the idea that elucidating the metabolic modifications that can either induce or inhibit tumor progression could be of immense significance for shaping new therapeutic approaches and preventative measures. We conclude that an extensive effort must be directed towards research for the standardization of drugs that specifically target proteins such as SDH and SUCNR1, but also TRAP1, PDH, ERK1/2, STAT3 and the HIF1-α catabolism.

| S-EPMC10216699 | biostudies-literature

Inhibition of Succinate Dehydrogenase by Pesticides (SDHIs) and Energy Metabolism.

Project description:Succinate dehydrogenase (SDH) is one of the enzymes of the tricarboxylic acid cycle (Krebs cycle) and complex II of the mitochondrial respiratory chain. A class of fungicides (SDHIs) targets the complex II reaction in the SDH. A large number of those in use have been shown to inhibit SDH in other phyla, including humans. This raises questions about possible effects on human health and non-target organisms in the environment. The present document will address metabolic consequences in mammals; it is neither a review on SDH nor is it about the toxicology of SDHIs. Most clinically relevant observations are linked to a severe decrease in SDH activity. Here we shall examine the mechanisms for compensating a loss of SDH activity and their possible weaknesses or adverse consequences. It can be expected that a mild inhibition of SDH will be compensated by the kinetic properties of this enzyme, but this implies a proportionate increase in succinate concentration. This would be relevant for succinate signaling and epigenetics (not reviewed here). With regard to metabolism, exposure of the liver to SDHIs would increase the risk for non-alcoholic fatty liver disease (NAFLD). Higher levels of inhibition may be compensated by modification of metabolic fluxes with net production of succinate. SDHIs are much more soluble in lipids than in water; consequently, a different diet composition between laboratory animals and humans is expected to influence their absorption.

| S-EPMC9962667 | biostudies-literature

Epithelial to mesenchymal transition (EMT) is associated with attenuation of succinate dehydrogenase (SDH) in breast cancer through reduced expression of <i>SDHC</i>.

Project description:BackgroundEpithelial to mesenchymal transition (EMT) is a well-characterized process of cell plasticity that may involve metabolic rewiring. In cancer, EMT is associated with malignant progression, tumor heterogeneity, and therapy resistance. In this study, we investigated the role of succinate dehydrogenase (SDH) as a potential key regulator of EMT.MethodsAssociations between SDH subunits and EMT were explored in gene expression data from breast cancer patient cohorts, followed by in-depth studies of SDH suppression as a potential mediator of EMT in cultured cells.ResultsWe found an overall inverse association between EMT and the SDH subunit C (SDHC) when analyzing gene expression in breast tumors. This was particularly evident in carcinomas of basal-like molecular subtype compared to non-basal-like tumors, and a low SDHC expression level tended to have a prognostic impact in those patients. Studies in cultured cells revealed that EMT was induced by SDH inhibition through SDHC CRISPR/Cas9 knockdown or by the enzymatic inhibitor malonate. Conversely, overexpression of EMT-promoting transcription factors TWIST and SNAI2 caused decreased levels of SDHB and C and reduced rates of SDH-linked mitochondrial respiration. Cells overexpressing TWIST had reduced mitochondrial mass, and the organelles were thinner and more fragmented compared to controls.ConclusionsOur findings suggest that downregulation of SDHC promotes EMT and that this is accompanied by structural remodeling of the mitochondrial organelles. This may confer survival benefits upon exposure to hostile microenvironment including oxidative stress and hypoxia during cancer progression.

| S-EPMC6544948 | biostudies-literature

Inhibition of Epithelial-Mesenchymal Transition Maintains Stemness in Human Amniotic Epithelial Cells.

Project description:Human amniotic epithelial cells (hAECs), which are a type of placental stem cell, express stem cell marker genes and are capable of differentiating into all three germ layers under appropriate culture conditions. hAECs are known to undergo TGF-β-dependent epithelial-mesenchymal transition (EMT); however, the impact of EMT on the stemness or differentiation of hAECs has not yet been determined. Here, we first confirmed that hAECs undergo EMT immediately after starting primary culture. Comprehensive transcriptome analysis using RNA-seq revealed that inhibition of TGF-β-dependent EMT maintained the expression of stemness-related genes, including NANOG and POU5F1, in hAECs. Moreover, the maintenance of stemness did not affect the nontumorigenic characteristics of hAECs. We showed for the first time that TGF-β-dependent EMT negatively affected the stemness of hAECs, providing novel insight into cellular processes of placental stem cells.

| S-EPMC9622541 | biostudies-literature

PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation.

Project description:Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1 and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration.

| S-EPMC4524786 | biostudies-literature

Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.

Project description:NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

| S-EPMC5121017 | biostudies-literature

AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition.

Project description:Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition. Here, we report that nuclear deformation induced by TGFβ is concomitant with increased phosphorylation of lamin A at Ser390, defective nuclear lamina and genome instability. AKT2 and Smad3 serve as the downstream effectors for TGFβ to induce nuclear deformation. AKT2 directly phosphorylates lamin A at Ser390, whereas Smad3 is required for AKT2 activation upon TGFβ stimulation. Expression of the lamin A mutant with a substitution of Ser390 to Ala or suppression of AKT2 or Smad3 prevents nuclear deformation and genome instability induced by TGFβ. These findings reveal a molecular mechanism for TGFβ-induced nuclear deformation and establish a role of nuclear deformation in genome instability during epithelial-mesenchymal transition.

| S-EPMC10291577 | biostudies-literature

Prostate epithelial Pten/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition.

Project description:Loss of PTEN and loss of TP53 are common genetic aberrations occurring in prostate cancer. PTEN and TP53 contribute to the regulation of self-renewal and differentiation in prostate progenitors, presumptive tumor initiating cells for prostate cancer. Here we characterize the transformed phenotypes resulting from deletion of the Pten and TP53 tumor suppressors in prostate epithelium. Using the PB-Cre4(+)Pten(fl/fl)TP53(fl/fl) model of prostate cancer, we describe the histological and metastatic properties of primary tumors, transplanted primary tumor cells, and clonal cell lines established from tumors. Adenocarcinoma was the major primary tumor type that developed, which progressed to lethal sarcomatoid carcinoma at approximately 6 months of age. In addition, basal carcinomas and prostatic urothelial carcinomas were observed. We show that tumor heterogeneity resulted, at least in part, from the transformation of multipotential progenitors. CK8+ luminal epithelial cells were capable of undergoing epithelial to mesenchymal transition in vivo to sarcomatoid carcinomas containing osseous metaplasia. Metastasis rarely was observed from primary tumors, but metastasis to lung and lymph nodes occurred frequently from orthotopic tumors initiated from a biphenotypic clonal cell line. Androgen deprivation influenced the differentiated phenotypes of metastases. These data show that one functional consequence of Pten/TP53 loss in prostate epithelium is lineage plasticity of transformed cells.

| S-EPMC3123810 | biostudies-other

Iron metabolism regulation of epithelial-mesenchymal transition in idiopathic pulmonary fibrosis.

Project description:BackgroundIron overload has been found in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and is thought to be involved in disease progression; however, the underlying mechanism is complex and not yet fully understood. We sought to assess the in vitro role of iron in the progression of fibrosis in lung epithelial cells, and examine the possible regulation of iron and IPF.MethodsErastin was used to establish a cell model of iron accumulation in mouse lung epithelial cell line 12 (MLE-12). A Cell Counting Kit-8 assay and annexin V staining were applied to measure cell viability and apoptosis, quantitative polymerase chain reaction (qPCR) and quantitative immunoblot analysis of the protein was conducted to analyze the expression of E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA), Vimentin and β-Actin. The autophagy was visualized by microtubule-associated protein 1A/1B-light chain 3 (LC3) staining and western blot.ResultsThe results showed that cell proliferation was significantly inhibited and apoptotic and necrotic cells were significantly increased with 2 µM of erastin treatment. Western blotting showed that reactive oxygen species (ROS) production and the level of heme oxygenase-1 were increased in the cells. Epithelial-mesenchymal transition (EMT) represented by the suppression of E-cadherin and the upregulation of α-smooth muscle actin (α-SMA) and Vimentin was induced by erastin. Additionally, autophagy represented by activated LC3B and up-regulated Beclin-1 were also induced by erastin. To further ascertain the role of autophagy in erastin-induced EMT, chloroquine, which is an autophagy inhibitor, was employed, and was found to effectively reduce EMT in this process.ConclusionsThese results support the role of the enhanced accumulation of iron as a mechanism for increasing the vulnerability of lung epithelial cells to iron-driven oxidant injury that triggers further autophagy during EMT.

| S-EPMC8756254 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data