scholarly journals PKM2, a Central Point of Regulation in Cancer Metabolism

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Nicholas Wong ◽  
Jason De Melo ◽  
Damu Tang
Keyword(s):  
Protein Tyrosine Kinase ◽  
Cancer Metabolism ◽  
Kinase Activity ◽  
Aerobic Glycolysis ◽  
Active Form ◽  
Building Blocks ◽  
Atp Production ◽  
Complex Regulation ◽  
Rate Limiting ◽  
Glucose Metabolites

Aerobic glycolysis is the dominant metabolic pathway utilized by cancer cells, owing to its ability to divert glucose metabolites from ATP production towards the synthesis of cellular building blocks (nucleotides, amino acids, and lipids) to meet the demands of proliferation. The M2 isoform of pyruvate kinase (PKM2) catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. In the PK family, PKM2 is subjected to a complex regulation by both oncogenes and tumour suppressors, which allows for a fine-tone regulation of PKM2 activity. The less active form of PKM2 drives glucose through the route of aerobic glycolysis, while active PKM2 directs glucose towards oxidative metabolism. Additionally, PKM2 possesses protein tyrosine kinase activity and plays a role in modulating gene expression and thereby contributing to tumorigenesis. We will discuss our current understanding of PKM2's regulation and its many contributions to tumorigenesis.

scholarly journals Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells

2002 ◽  
Vol 364 (1) ◽  
pp. 309-315 ◽  
Author(s):  
Michael GUPPY ◽  
Peter LEEDMAN ◽  
XinLin ZU ◽  
Victoria RUSSELL
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Cancer Cell Line ◽  
Cell Types ◽  
Atp Production ◽  
Atp Turnover ◽  
Innovative System ◽  
Mcf 7

For the past 70 years the dominant perception of cancer metabolism has been that it is fuelled mainly by glucose (via aerobic glycolysis) and glutamine. Consequently, investigations into the diagnosis, treatment and the basic metabolism of cancer cells have been directed by this perception. However, the data on cancer metabolism are equivocal, and in this study we have sought to clarify the issue. Using an innovative system we have measured the total ATP turnover of the MCF-7 breast cancer cell line, the contributions to this turnover by oxidative and glycolytic ATP production and the contributions to the oxidative component by glucose, lactate, glutamine, palmitate and oleate. The total ATP turnover over approx. 5days was 26.8μmol of ATP·107 cells−1·h−1. ATP production was 80% oxidative and 20% glycolytic. Contributions to the oxidative component were approx. 10% glucose, 14% glutamine, 7% palmitate, 4% oleate and 65% from unidentified sources. The contribution by glucose (glycolysis and oxidation) to total ATP turnover was 28.8%, glutamine contributed 10.7% and glucose and glutamine combined contributed 40%. Glucose and glutamine are significant fuels, but they account for less than half of the total ATP turnover. The contribution of aerobic glycolysis is not different from that in a variety of other non-transformed cell types.

scholarly journals Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2308
Author(s):  
Jae Hyung Park ◽  
Woo Yang Pyun ◽  
Hyun Woo Park
Keyword(s):  
Signal Transduction ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Cancer Therapeutics ◽  
Building Blocks ◽  
Signal Transduction Pathways ◽  
Intermittent Fasting ◽  
Redox Potentials ◽  
Metabolic Phenotypes

Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo pathway, mediate metabolic gene expression and increase metabolic enzyme activities. Vice versa, deregulated metabolic pathways contribute to defects in cellular signal transduction pathways, which in turn provide energy, building blocks, and redox potentials for unrestrained cancer cell proliferation. Studies and clinical trials are being performed that focus on the inhibition of metabolic enzymes by small molecules or dietary interventions (e.g., fasting, calorie restriction, and intermittent fasting). Similar to genetic heterogeneity, the metabolic phenotypes of cancers are highly heterogeneous. This heterogeneity results from diverse cues in the tumor microenvironment and genetic mutations. Hence, overcoming metabolic plasticity is an important goal of modern cancer therapeutics. This review highlights recent findings on the metabolic phenotypes of cancer and elucidates the interactions between signal transduction pathways and metabolic pathways. We also provide novel rationales for designing the next-generation cancer metabolism drugs.

scholarly journals The Crosstalk Between Cell Adhesion and Cancer Metabolism

2019 ◽  
Vol 20 (8) ◽  
pp. 1933 ◽  
Author(s):  
Bárbara Sousa ◽  
Joana Pereira ◽  
Joana Paredes
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Redox Homeostasis ◽  
Building Blocks ◽  
Metabolic Reprogramming ◽  
Special Focus ◽  
Oncogenic Signaling ◽  
Cell Cell

Cancer cells preferentially use aerobic glycolysis over mitochondria oxidative phosphorylation for energy production, and this metabolic reprogramming is currently recognized as a hallmark of cancer. Oncogenic signaling frequently converges with this metabolic shift, increasing cancer cells’ ability to produce building blocks and energy, as well as to maintain redox homeostasis. Alterations in cell–cell and cell–extracellular matrix (ECM) adhesion promote cancer cell invasion, intravasation, anchorage-independent survival in circulation, and extravasation, as well as homing in a distant organ. Importantly, during this multi-step metastatic process, cells need to induce metabolic rewiring, in order to produce the energy needed, as well as to impair oxidative stress. Although the individual implications of adhesion molecules and metabolic reprogramming in cancer have been widely explored over the years, the crosstalk between cell adhesion molecular machinery and metabolic pathways is far from being clearly understood, in both normal and cancer contexts. This review summarizes our understanding about the influence of cell–cell and cell–matrix adhesion in the metabolic behavior of cancer cells, with a special focus concerning the role of classical cadherins, such as Epithelial (E)-cadherin and Placental (P)-cadherin.

Probing the Substrate Promiscuity of Isopentenyl Phosphate Kinase as a Platform for Hemiterpene Analogue Production

2019 ◽  
Author(s):  
Sean Lund ◽  
Taylor Courtney ◽  
Gavin Williams
Keyword(s):  
Synthetic Biology ◽  
Building Blocks ◽  
Isoprenoid Biosynthesis ◽  
Thermoplasma Acidophilum ◽  
Substrate Promiscuity ◽  
Enzymatic Pathways ◽  
First Time ◽  
Rate Limiting ◽  
Alcohol Dependent ◽  
Isopentenyl Phosphate

Isoprenoids are a large class of natural products with wide-ranging applications. Synthetic biology approaches to the manufacture of isoprenoids and their new-to-nature derivatives are limited due to the provision in Nature of just two hemiterpene building blocks for isoprenoid biosynthesis. To address this limitation, artificial chemo-enzymatic pathways such as the alcohol-dependent hemiterpene pathway (ADH) serve to leverage consecutive kinases to convert exogenous alcohols to pyrophosphates that could be coupled to downstream isoprenoid biosynthesis. To be successful, each kinase in this pathway should be permissive of a broad range of substrates. For the first time, we have probed the promiscuity of the second enzyme in the ADH pathway, isopentenyl phosphate kinase from Thermoplasma acidophilum, towards a broad range of acceptor monophosphates. Subsequently, we evaluate the suitability of this enzyme to provide non-natural pyrophosphates and provide a critical first step in characterizing the rate limiting steps in the artificial ADH pathway.<br>

scholarly journals Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ling Jin ◽  
Eun-Yeong Kim ◽  
Tae-Wook Chung ◽  
Chang Woo Han ◽  
So Young Park ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Pyruvate Dehydrogenase Kinase ◽  
Cancer Drug ◽  
Potential Candidate ◽  
Mitochondrial Ros

AbstractMost cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.

scholarly journals Investigation of energy metabolic dynamism in hyperthermia-resistant ovarian and uterine cancer cells under heat stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Taisei Kanamori ◽  
Natumi Miyazaki ◽  
Shigeki Aoki ◽  
Kousei Ito ◽  
Akihiro Hisaka ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Uterine Cancer ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Ubiquitin Pathway ◽  
Atp Production ◽  
Skov3 Cells ◽  
Pathway Analyses ◽  
Rate Limiting ◽  
Glycolytic Rate ◽  
The Warburg Effect

AbstractDespite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. In a previous study, we found that sensitivity to hyperthermia varied between ovarian and uterine cancer cell lines. Upon hyperthermia, glycolytic enzymes decreased in hyperthermia-resistant SKOV3 cells. However, the mechanisms of glycolysis inhibition and their relationship with thermoresistance remain to be explored. In this study, metabolomic analysis indicated the downregulation of glycolytic metabolites in SKOV3 cells after hyperthermia. Proteomic and pathway analyses predicted that the ubiquitin pathway was explicitly activated in resistant SKOV3 cells, compared with hyperthermia-sensitive A2780 cells, and STUB1, a ubiquitin ligase, potentially targeted PKM, a glycolytic rate-limiting enzyme. PKM is degraded via ubiquitination upon hyperthermia. Although glycolysis is inactivated by hyperthermia, ATP production is maintained. We observed that oxygen consumption and mitochondrial membrane potential were activated in SKOV3 cells but suppressed in A2780 cells. The activation of mitochondria could compensate for the loss of ATP production due to the suppression of glycolysis by hyperthermia. Although the physiological significance has not yet been elucidated, our results demonstrated that metabolomic adaptation from the Warburg effect to mitochondrial oxidative phosphorylation could contribute to thermoresistance in ovarian and uterine cancer cells.

scholarly journals Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3018
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Kevin Zhai ◽  
Elizabeth Varghese ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effective Prevention ◽  
Anti Cancer ◽  
Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

scholarly journals HO-1 Modulates Aerobic Glycolysis through LDH in Prostate Cancer Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 966
Author(s):  
Florencia Cascardo ◽  
Nicolás Anselmino ◽  
Alejandra Páez ◽  
Estefanía Labanca ◽  
Pablo Sanchis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Aerobic Glycolysis ◽  
Heme Oxygenase 1 ◽  
Free Survival ◽  
Atp Production ◽  
Inflammatory Damage ◽  
Extracellular Lactate ◽  
Cellular Energetics ◽  
Lactate Levels

Prostate cancer (PCa) is the second most diagnosed malignancy and the fifth leading cause of cancer associated death in men worldwide. Dysregulation of cellular energetics has become a hallmark of cancer, evidenced by numerous connections between signaling pathways that include oncoproteins and key metabolic enzymes. We previously showed that heme oxygenase 1 (HO-1), a cellular homeostatic regulator counteracting oxidative and inflammatory damage, exhibits anti-tumoral activity in PCa cells, inhibiting cell proliferation, migration, tumor growth and angiogenesis. The aim of this study was to assess the role of HO-1 on the metabolic signature of PCa. After HO-1 pharmacological induction with hemin, PC3 and C4-2B cells exhibited a significantly impaired cellular metabolic rate, reflected by glucose uptake, ATP production, lactate dehydrogenase (LDH) activity and extracellular lactate levels. Further, we undertook a bioinformatics approach to assess the clinical significance of LDHA, LDHB and HMOX1 in PCa, identifying that high LDHA or low LDHB expression was associated with reduced relapse free survival (RFS). Interestingly, the shortest RFS was observed for PCa patients with low HMOX1 and high LDHA, while an improved prognosis was observed for those with high HMOX1 and LDHB. Thus, HO-1 induction causes a shift in the cellular metabolic profile of PCa, leading to a less aggressive phenotype of the disease.

scholarly journals Development of the Sensing Platform for Protein Tyrosine Kinase Activity

Biosensors ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 240
Author(s):  
Lan-Yi Wei ◽  
Wei Lin ◽  
Bey-Fen Leo ◽  
Lik-Voon Kiew ◽  
Chia-Ching Chang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Significant Inhibition ◽  
Tyrosine Kinase Activity ◽  
Protein Tyrosine ◽  
Sensing Platform ◽  
Relative Standard ◽  
Protein Tyrosine Kinase Activity

A miniature tyrosinase-based electrochemical sensing platform for label-free detection of protein tyrosine kinase activity was developed in this study. The developed miniature sensing platform can detect the substrate peptides for tyrosine kinases, such as c-Src, Hck and Her2, in a low sample volume (1–2 μL). The developed sensing platform exhibited a high reproducibility for repetitive measurement with an RSD (relative standard deviation) of 6.6%. The developed sensing platform can detect the Hck and Her2 in a linear range of 1–200 U/mL with the detection limit of 1 U/mL. The sensing platform was also effective in assessing the specificity and efficacies of the inhibitors for protein tyrosine kinases. This is demonstrated by the detection of significant inhibition of Hck (~88.1%, but not Her2) by the Src inhibitor 1, an inhibitor for Src family kinases, as well as the significant inhibition of Her2 (~91%, but not Hck) by CP-724714 through the platform. These results suggest the potential of the developed miniature sensing platform as an effective tool for detecting different protein tyrosine kinase activity and for accessing the inhibitory effect of various inhibitors to these kinases.

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