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

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

PROVIDER: PRJNA516704 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8479190.fastq.gz	Fastqsanger.gz
	SRR8479200.fastq.gz	Fastqsanger.gz
	SRR8479191.fastq.gz	Fastqsanger.gz
	SRR8479201.fastq.gz	Fastqsanger.gz
	SRR8479192.fastq.gz	Fastqsanger.gz

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

Project description: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.

2019-02-27 | GSE125538 | GEO

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

Project description: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 to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, 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 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.

| S-EPMC6379428 | biostudies-literature

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

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

2012-12-31 | GSE16816 | GEO

Hif1α-Dependent Uncoupling Of Glycolysis Suppresses Tumor Cell Proliferation

Project description:Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. Paradoxically, it remains unknown why lower glycolysis is compromised in human clear cell renal cell carcinomas (ccRCC), in which HIF1α acts a tumor suppressor by inhibiting cell autonomous proliferation. Here we found that unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

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Reduced Nicotinamide Mononucleotide (NMNH) Potently Enhances NAD+, Suppresses Glycolysis and Cell Growth

Project description:In the present study, we developed a chemical method to produce dihydro nicotinamide mononucleotide (NMNH), which is the reduced-form of nicotinamide mononucleotide (NMN). We demonstrated that NMNH was a better nicotinamide adenine dinucleotide (NAD+) enhancer compared to NMN both in vitro and in vivo mediated by mononucleotide adenylyltransferase (NMNAT). Additionally, NMNH increased the reduced NAD (NADH) levels in cells and in mouse liver. Metabolomic analysis revealed that NMNH inhibited glycolysis and TCA cycle. In vitro experiments demonstrated that NMNH induced cell cycle arrest and suppressed cell growth. Nevertheless, NMNH treatment did not cause observable difference in mice. Taken together, our work demonstrates that NMNH is a potent NAD+ enhancer, and suppresses glycometabolism and cell growth.

2022-02-25 | PXD022547 | Pride

Gene expression data of 135 patients presenting colorectal adenoma

Project description:Gene expression profiles of 135 patients presenting with colorectal adenomas during surgery or colonoscopy were obtained using Affymetrix U133+ arrays.

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Sinorhizobium medicae strain:135

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