IDH3α regulates one-carbon metabolism in glioblastoma

Mutation or transcriptional up-regulation of isocitrate dehydrogenases 1 and 2 (IDH1andIDH2) promotes cancer progression through metabolic reprogramming and epigenetic deregulation of gene expression. Here, we demonstrate that IDH3α, a subunit of the IDH3 heterotetramer, is elevated in glioblastoma (GBM) patient samples compared to normal brain tissue and promotes GBM progression in orthotopic glioma mouse models. IDH3α loss of function reduces tricarboxylic acid (TCA) cycle turnover and inhibits oxidative phosphorylation. In addition to its impact on mitochondrial energy metabolism, IDH3α binds to cytosolic serine hydroxymethyltransferase (cSHMT). This interaction enhances nucleotide availability during DNA replication, while the absence of IDH3α promotes methionine cycle activity,S-adenosyl methionine generation, and DNA methylation. Thus, the regulation of one-carbon metabolism via an IDH3α-cSHMT signaling axis represents a novel mechanism of metabolic adaptation in GBM.

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High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates with Lower Survival

10.1101/2021.10.07.463555 ◽

2021 ◽

Author(s):

Kimberly M Stanke ◽

Carrick Wilson ◽

Srivatsan Kidambi

Keyword(s):

Gene Expression ◽

Aerobic Glycolysis ◽

Treatment Options ◽

Lactate Production ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

High Expression ◽

Low Grade ◽

Normal Brain ◽

Expression Levels

Glioblastoma (GBM), the most aggressive brain tumor, is associated with a median survival at diagnosis of 16-20 months and limited treatment options. The key hallmark of GBM is altered tumor metabolism and marked increase in the rate of glycolysis. Aerobic glycolysis along with elevated glucose consumption and lactate production supports rapid cell proliferation and GBM growth. In this study, we examined the gene expression profile of metabolic targets in GBM samples from patients with low grade glioma (LGG) and GBM. We found that gene expression of glycolytic enzymes is up-regulated in GBM samples and significantly associated with an elevated risk for developing GBM. Our findings of clinical outcomes showed that GBM patients with high expression of HK2 and PKM2 in the glycolysis related genes and low expression of genes involved in mitochondrial metabolism-SDHB and COX5A related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), respectively, was associated with poor patient overall survival. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in GBM compared to LGG but was lower compared to normal brain. The fact that in GBM the expression levels of TCA cycle and OXPHOS-related genes are higher than those in LGG patients suggests the metabolic shift in GBM cells when progressing from LGG to GBM. These results are an important step forward in our understanding of the role of metabolic reprogramming in glioma as drivers of the tumor and could be potential prognostic targets in GBM therapies.

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Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

Clinical Chemistry ◽

10.1373/clinchem.2018.299651 ◽

2019 ◽

Vol 65 (9) ◽

pp. 1090-1101 ◽

Cited By ~ 17

Author(s):

Sugarniya Subramaniam ◽

Varinder Jeet ◽

Judith A Clements ◽

Jennifer H Gunter ◽

Jyotsna Batra

Keyword(s):

Fatty Acid ◽

Signaling Pathways ◽

Tumor Cells ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

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Glucose Metabolic Dysfunction in Neurodegenerative Diseases—New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming

International Journal of Molecular Sciences ◽

10.3390/ijms22115887 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5887

Author(s):

Rongrong Han ◽

Jing Liang ◽

Bing Zhou

Keyword(s):

Glucose Metabolism ◽

Neurodegenerative Disease ◽

Energy Demand ◽

High Energy ◽

Adult Brain ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Normal Brain ◽

Metabolic Dysfunction ◽

Lateral Sclerosis

Glucose is the main circulating energy substrate for the adult brain. Owing to the high energy demand of nerve cells, glucose is actively oxidized to produce ATP and has a synergistic effect with mitochondria in metabolic pathways. The dysfunction of glucose metabolism inevitably disturbs the normal functioning of neurons, which is widely observed in neurodegenerative disease. Understanding the mechanisms of metabolic adaptation during disease progression has become a major focus of research, and interventions in these processes may relieve the neurons from degenerative stress. In this review, we highlight evidence of mitochondrial dysfunction, decreased glucose uptake, and diminished glucose metabolism in different neurodegeneration models such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). We also discuss how hypoxia, a metabolic reprogramming strategy linked to glucose metabolism in tumor cells and normal brain cells, and summarize the evidence for hypoxia as a putative therapy for general neurodegenerative disease.

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Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells

npj Systems Biology and Applications ◽

10.1038/s41540-020-00161-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Selva Rupa Christinal Immanuel ◽

Avinash D. Ghanate ◽

Dharmeshkumar S. Parmar ◽

Ritu Yadav ◽

Riya Uthup ◽

...

Keyword(s):

Genetic Basis ◽

Cell Function ◽

Tca Cycle ◽

Integrated Approach ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Whole Exome ◽

Low Concentrations ◽

Differential Killing ◽

Glioblastoma Cell Lines

AbstractMetabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, malate aspartate shunt, and oxidative phosphorylation pathways. The differential killing of TMZ resistant NSP by Rotenone at low concentrations with an IC50 value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC50 value of 1.8 mM was thus identified using our integrated systems-based approach.

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Serine Starvation Silences Estrogen Receptor Signaling through Histone Hypoacetylation

10.1101/2021.09.05.459037 ◽

2021 ◽

Author(s):

Albert M. Li ◽

Yang Li ◽

Bo He ◽

Haowen Jiang ◽

Yaniel Ramirez ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Progression ◽

Estrogen Receptor Alpha ◽

Metabolic Stress ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Specific Gene ◽

Acetyl Coa ◽

Histone Hypoacetylation

ABSTRACTEstrogen receptor (ER) plays important roles in regulating normal development and female reproductive system function. Loss of ER pathway activity is a hallmark of breast cancer progression, associated with accelerated tumor proliferation and resistance to endocrine therapy. How ER loss occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in solid tumors, downregulates estrogen receptor alpha (ERα) expression, represses transcriptional targets such as progesterone receptor (PR), and reduces sensitivity to antiestrogens, suggesting a transition of ER-positive (ER+) breast cancer cells to an ER/PR-negative (ER-/PR-) state. ER downregulation under serine starvation is accompanied by a global loss of histone acetylation. These chromatin changes are driven by metabolic reprogramming triggered by serine starvation, particularly lower glucose flux through glycolysis and the TCA cycle, leading to reduced acetyl-CoA levels and histone hypoacetylation. Supplementation with acetate or glycerol triacetate (GTA), precursors of acetyl-CoA, restores H3K27 acetylation and ERα expression under serine starvation. Therefore, a major consequence of serine starvation in breast cancer could be global chromatin changes that influence lineage-specific gene expression.

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The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-10006-2 ◽

2022 ◽

Author(s):

Anna Sebestyén ◽

Titanilla Dankó ◽

Dániel Sztankovics ◽

Dorottya Moldvai ◽

Regina Raffay ◽

...

Keyword(s):

Tumor Progression ◽

Cancer Progression ◽

Tumor Biology ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Metabolic Phenotyping ◽

Regulatory Pathways ◽

Metabolic Plasticity ◽

Cancer Management ◽

Mtor Kinase

AbstractDespite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.

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Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction

Nutrients ◽

10.3390/nu13051637 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1637

Author(s):

Michael F. Coleman ◽

Ciara H. O’Flanagan ◽

Alexander J. Pfeil ◽

Xuewen Chen ◽

Jane B. Pearce ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Carbon Metabolism ◽

Triple Negative ◽

Metabolic Reprogramming ◽

Breast Cancers ◽

Nucleotide Biosynthesis ◽

Tumor Weight ◽

One Carbon Metabolism

Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. Methods: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. Results: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. Conclusions: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.

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Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities

Cancers ◽

10.3390/cancers12061436 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1436 ◽

Cited By ~ 2

Author(s):

Alice Turdo ◽

Gaetana Porcelli ◽

Caterina D’Accardo ◽

Simone Di Franco ◽

Francesco Verona ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Therapeutic Approaches ◽

Current Therapies ◽

Oxidative Phenotype

Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells—termed cancer stem cells (CSCs)—which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.

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Phosphatases: The New Brakes for Cancer Development?

Enzyme Research ◽

10.1155/2012/659649 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 32

Author(s):

Qingxiu Zhang ◽

Francois X. Claret

Keyword(s):

Cancer Progression ◽

Pi3k Pathway ◽

Akt Signaling ◽

Cancer Development ◽

Inositol Polyphosphate ◽

Loss Of Function ◽

Signaling Axis ◽

Phosphatase 2A ◽

Src Homology ◽

Phosphatase And Tensin Homologue

The phosphatidylinositol 3-kinase (PI3K) pathway plays a pivotal role in the maintenance of processes such as cell growth, proliferation, survival, and metabolism in all cells and tissues. Dysregulation of the PI3K/Akt signaling pathway occurs in patients with many cancers and other disorders. This aberrant activation of PI3K/Akt pathway is primarily caused by loss of function of all negative controllers known as inositol polyphosphate phosphatases and phosphoprotein phosphatases. Recent studies provided evidence of distinct functions of the four main phosphatases—phosphatase and tensin homologue deleted on chromosome 10 (PTEN), Src homology 2-containing inositol 5′-phosphatase (SHIP), inositol polyphosphate 4-phosphatase type II (INPP4B), and protein phosphatase 2A (PP2A)—in different tissues with respect to regulation of cancer development. We will review the structures and functions of PTEN, SHIP, INPP4B, and PP2A phosphatases in suppressing cancer progression and their deregulation in cancer and highlight recent advances in our understanding of the PI3K/Akt signaling axis.

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Metabolic Constrains Rule Metastasis Progression

Cells ◽

10.3390/cells9092081 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2081

Author(s):

Niccolo’ Roda ◽

Valentina Gambino ◽

Marco Giorgio

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Primary Tumor ◽

Distant Metastases ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Surgical Removal ◽

Metastatic Progression ◽

Metastasis Formation ◽

Primary Tumor Site

Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression.

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