Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting tumor mitochondrial metabolism overcomes resistance to antiangiogenics

ABSTRACT: Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how novel multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors down-regulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic and phosphoproteomic study revealed that this metabolic switch is mediated by down-regulation of HIF1α and AKT and up-regulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, especially in a sequential schedule, leading to metabolic synthetic lethality. Our study uncovers new mechanistic insights in the process of tumor resistance to TKIs, and may have clinical applicability.

ORGANISM(S): Mus musculus

PROVIDER: GSE80778 | GEO | 2019/04/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Targeting tumor mitochondrial metabolism overcomes resistance to antiangiogenics

Project description:Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how novel multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors down-regulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic and phosphoproteomic study revealed that this metabolic switch is mediated by down-regulation of HIF1α and AKT and up-regulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, especially in a sequential schedule, leading to metabolic synthetic lethality. Our study uncovers new mechanistic insights in the process of tumor resistance to TKIs, and may have clinical applicability

2022-03-02 | PXD004071 | Pride

MITOCHONDRIAL Akt REGULATION OF HYPOXIC METABOLIC REPROGRAMMING

Project description:Hypoxia is a driver of aggressive tumor behavior, but the mechanisms are not completely understood. In a global phosphoproteomics screen, we now demonstrate that hypoxia induces the recruitment of Akt2 to tumor mitochondria, and Akt phosphorylation of pyruvate dehydrogenase kinase (PDK1) on Thr346. In turn, Akt-phosphorylated PDK1 shuts off oxidative phosphorylation via phosphorylation of the pyruvate dehydrogenase complex, and reprograms tumor metabolism towards glycolysis. Akt-phosphorylation of PDK1 is required to prevent autophagy, maintain cell viability and support tumor cell proliferation in hypoxia, in vivo. Therefore, mitochondrial Akt is a pathophysiologic switch for tumor adaptation in hypoxia.

2016-04-20 | MSV000079671 | MassIVE

Functions of OGDH in primed human embryonic stem cells.

Project description:Human embryonic stem cells (hESCs) can self-renew infinitely, or differentiate into the three germ layer lineages in vitro with certain cues, holding great promise to model early human embryo development ex vivo.It is wildly accepted that hESCs take advantage of both glycolysis and mitochondrial respiration to favor the naïve pluripotency, while prefer glycolysis to support the primed pluripotency. Thus, the function of mitochondrial respiration in primed hESCs has been underestimated for a long time, and has not been fully understood yet. Herein, we report that the adenosine triphosphate (ATP) production rate is comparable between mitochondrial respiration and glycolysis, suggesting that mitoATP serves as one of the major sources of the ATP pool in primed hESCs. Next, we constructed a OGDH knockdown cell line whose ability of mitochondrial respiration was impired. Of note, OGDH deficiency led to the exit of primed pluripotency accompanied by cell death.Collectively, the current study unveils that OGDH acts as a key regulator to fine-tune the abundance of TCA cycle metabolites to ensure the mitochondrial respiration activity in primed hESCs, and highlights the pivotal roles of mitochondrial respiration in terms of ATP production and the maintenance of primed pluripotency.

2022-01-30 | GSE195539 | GEO

A bioenergetic shift is required for spermatogonial differentiation

Project description:A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference of bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid-induced differentiation. To accommodate this elevated energy demand, retinoic acid signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. In addition, inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway blocked the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon retinoic acid-induced differentiation by both RNA-seq analyses and quantitative proteomics. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration which is required for spermatogonial proliferation and differentiation.

2021-09-09 | PXD019136 | Pride

Role of histone demethylase LSD1 in hepatic cancer metabolism

Project description:Transcriptome analysis of LSD1-depleted HepG2 cells revealed that LSD1 regulates the expression of glycolytic and mitochondrial metabolism genes. We found that LSD1 is an important regulator of glycolysis and mitochondrial respiration in hepatoma. We depleted LSD1 in HepG2 human hepatoma cells using two different siRNAs, and then carried out an expression microarray experiment.

2015-05-21 | E-GEOD-69075 | biostudies-arrayexpress

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Project description:Metabolic reprograming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves a key regulator of cellular metabolism. As part of nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR, and directly affects mitochondrial oxidative phosphorylation via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1α. NM1 depletion leads to a suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae and redistribution of mitochondria within a cell, which is associated with reduced expression of oxidative phosphorylation genes, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics. This leads to a metabolic reprogramming of NM1 KO cells from oxidative phosphorylation to aerobic glycolysis and with that associated metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increase in glucose uptake, lactate production and intracellular acidity. We show that NM1 KO cells are able to form solid tumors in a nude mouse model even though they have supressed PI3K/Akt/mTOR signalling pathway suggesting that the metabolic switch towards aerobic glycolysis provide a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as tumor suppressor and that NM1 depletion may be partly responsible for the Warburg effect at the early onset of tumorigenesis.

2023-07-13 | GSE236679 | GEO

Nuclear Myosin 1 depletion leads to a metabolic reprogramming of cells and tumorigenesis in mice

2022-06-27 | GSE206858 | GEO

Combinatorial targeting of glycolysis and oxidative phosphorylation suppresses tumor growth and metastases.

Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)

2012-12-31 | E-GEOD-16816 | biostudies-arrayexpress

The Oligostilbene Gnetin-H is a Novel Glycolysis Inhibitor that Regulates Thioredoxin Interacting Protein Expression and Synergizes with OXPHOS Inhibitor in Cancer Cells

Project description:Since aerobic glycolysis has been first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism sparked the interest of scientists around the world as it might offer new avenues of treatments for malignant cells. Our current study claims the discovery of Gnetin-H (GH) as a novel glycolysis inhibitor that can decrease metabolic activity and lactic acid synthesis and displays a strong cytostatic effect in melanoma and glioblastoma cells. Compared to most of the other glycolysis inhibitors used in combination with the complex-1 mitochondrial inhibitor Phenformin, GH more potently inhibited cell growth. RNA-Seq with the T98G glioblastoma cell line treated with GH showed more than an 80-fold reduction in Thioredoxin Interacting Protein (TXNIP) expression indicating that GH has a direct effect in regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with Phenformin also substantially enhanced levels of p-AMPK, a marker of metabolic catastrophe. These findings suggest that the concurrent use of the glycolytic inhibitor GH with a complex-1 mitochondrial inhibitor could be used as a powerful tool to induce metabolic catastrophe in cancer cells and reduce their growth.

2023-05-17 | GSE224692 | GEO

Role of histone demethylase LSD1 in hepatic cancer metabolism

2015-05-21 | GSE69075 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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