Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MiR-135 suppresses glycolysis and promotes adaptation to metabolic stress in pancreatic cancer cells by targeting phosphofructokinase-1

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt and survive in metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue and represses aerobic glycolysis. Mechanistically, we found that miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 deficient PDAC cells preferentially use glutamine carbon to replenish the TCA cycle, and miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumour growth in vivo. Consistent with these findings, patient pancreatic cancer tissue displays decreased PFK1 level compared to adjacent normal tissue. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumour microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125538 | GEO | 2019/02/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer [mouse]

Project description:Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.

2020-05-20 | GSE150874 | GEO

Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer [human]

2020-05-20 | GSE150873 | GEO

Pancreatic Tumor Microenvironment Maintains Tumor Growth through Nucleosides Secretion

Project description:Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for PDAC survival upon glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in an NUFIP1-depenent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

2021-10-19 | GSE185750 | GEO

Metabolic state determines drug response in liver cancer

Project description:Drug resistance is one of the most challenging problems in liver cancer research. The hepatocellular carcinoma cell line HLE is highly dependent on exogenous glutamine for proliferation. In this cell line, we have found that glutamine deprivation leads to proliferation arrest, phosphorylation of extracellular signal-regulated kinase (ERK), and metabolic alterations at gene, protein, metabolite levels. Interestingly, while HLE cells respond to kinase inhibitors in their unperturbed metabolic state, they display pro-tumourigenic phenotypes such as increased aerobic glycolysis and proliferation when treated with inhibitors of MAPK/ERK pathway in the impaired metabolic state induced by glutamine deprivation. Thus, the aim of this microarray analysis is to determine the genomic alterations that accompany glutamine deprivation and treatment with pERK inhibitor U0126. The anticipated alterations could shed light on novel molecular mechanisms underlying drug resistance, and may be useful for predicting therapeutic response in liver cancer.

2018-11-29 | GSE123062 | GEO

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

p53 promotes cancer cell adaptation to glutamine deprivation by upregulating Slc7a3 to increase arginine uptake

Project description:Cancer cells heavily depend on the amino acid, glutamine, to meet the demands associated with growth and proliferation. Due to its rapid consumption, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation using RNA-seq analysis. We show that Slc7a3, an arginine transporter, is significantly induced by p53. We show the concomitant rise in intracellular arginine levels following glutamine deprivation is dependent on p53. The influx of arginine has minimal effect on known metabolic pathways upon glutamine deprivation. Instead, we found arginine serves as an effector for mTORC1 activation to promote in vitro and in vivo cell growth in response to glutamine starvation. Therefore, we identify a novel p53-inducible gene that contributes to the metabolic stress response.

2019-05-15 | GSE125782 | GEO

Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS low Q]

Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.

2017-12-30 | GSE81643 | GEO

Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS high Q]

2017-12-30 | GSE81642 | GEO

Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [low versus high Q]

2017-12-30 | GSE81641 | GEO

A role for p53 in the adaptation to glutamine starvation through the expression of Slc1a3

Project description:Numerous mechanisms to support cells under conditions of transient nutrient starvation have been described. The tumor suppressor protein p53 can contribute to the adaptation of cells to metabolic stress through various mechanisms that may help cancer cell survival in nutrient limiting conditions. We show here that p53 helps cancer cells to survive glutamine starvation by promoting the expression of SLC1A3, an aspartate/glutamate transporter that allows the utilization of aspartate to support cells in the absence of extracellular glutamine. Under glutamine deprivation, SLC1A3 expression maintains electron transport chain and tricarboxylic acid cycle activity, promoting de novo glutamate, glutamine and nucleotide synthesis to rescue cell viability. Tumor cells with high levels of SLC1A3 expression are resistant to glutamine starvation and SLC1A3 depletion retards the growth of these cells in vitro and in vivo, suggesting a therapeutic potential for SLC1A3 inhibition.

2018-06-28 | GSE116087 | 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