scholarly journals Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1731 ◽  
Author(s):  
Carina Neitzel ◽  
Philipp Demuth ◽  
Simon Wittmann ◽  
Jörg Fahrer
Keyword(s):  
Colorectal Cancer ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Dietary Factors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Driver Mutations ◽  
The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

scholarly journals Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species

2012 ◽  
Vol 287 (42) ◽  
pp. 35153-35160 ◽  
Author(s):  
Thomas R. Hurd ◽  
Yvonne Collins ◽  
Irina Abakumova ◽  
Edward T. Chouchani ◽  
Bartlomiej Baranowski ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Oxygen Species ◽  
Complex Activity ◽  
Cycle Enzyme ◽  
Dehydrogenase Complex

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O2̇̄), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O2̇̄ production, such as may occur under nutrient excess and low ATP demand, the increase in O2̇̄ and H2O2 may provide feedback signals to modulate mitochondrial metabolism.

scholarly journals The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhenhua Zeng ◽  
Qiaobing Huang ◽  
Liangfeng Mao ◽  
Jie Wu ◽  
Sheng An ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Metabolic Regulation ◽  
Pyruvate Dehydrogenase Complex ◽  
Aerobic Oxidation ◽  
Tca Cycle ◽  
Protective Effects ◽  
Multienzyme Complex ◽  
Therapeutic Drugs ◽  
Dehydrogenase Complex

Anaerobic glycolysis is the process by which glucose is broken down into pyruvate and lactate and is the primary metabolic pathway in sepsis. The pyruvate dehydrogenase complex (PDHC) is a multienzyme complex that serves as a critical hub in energy metabolism. Under aerobic conditions, pyruvate translocates to mitochondria, where it is oxidized into acetyl-CoA through the activation of PDHC, thereby accelerating aerobic oxidation. Both phosphorylation and acetylation affect PDHC activity and, consequently, the regulation of energy metabolism. The mechanisms underlying the protective effects of PDHC in sepsis involve the regulation on the balance of lactate, the release of inflammatory mediators, the remodeling of tricarboxylic acid (TCA) cycle, as well as on the improvement of lipid and energy metabolism. Therapeutic drugs that target PDHC activation for sepsis treatment include dichloroacetate, thiamine, amrinone, TNF-binding protein, and ciprofloxacin. In this review, we summarize the recent findings regarding the metabolic regulation of PDHC in sepsis and the therapies targeting PDHC for the treatment of this condition.

Inhibition of Pyruvate Dehydrogenase Kinase as a Therapeutic Strategy against Cancer

2018 ◽  
Vol 18 (6) ◽  
pp. 444-453 ◽  
Author(s):  
Swatishree Sradhanjali ◽  
Mamatha M. Reddy
Keyword(s):  
Glucose Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Metabolic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
Glutamine Metabolism ◽  
Altered Glucose ◽  
Elevated Expression ◽  
Related Drug

Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules required for continuous proliferation. Glucose metabolism is frequently reprogrammed in several tumors in addition to fatty acid, amino acid and glutamine metabolism. Pyruvate Dehydrogenase Kinase (PDK) is a gatekeeper enzyme involved in altered glucose metabolism in tumors. There are four isoforms of PDK (1 to 4) in humans. PDK phosphorylates E1α subunit of pyruvate dehydrogenase complex (PDC) and inactivates it. PDC decarboxylates pyruvate to acetyl CoA, which is further metabolized in mitochondria. Overexpression of PDK was observed in several tumors and is frequently associated with chemotherapy related drug resistance, invasion and metastasis. Elevated expression of PDK leads to a shift in glucose metabolism towards glycolysis instead of oxidative phosphorylation. This review summarizes recent literature related to the role of PDKs in cancer and their inhibition as a strategy. In particular, we discuss the role of PDK in tumor progression, metabolic reprogramming in stem cells, and their regulation by miRNAs and lncRNAs, oncogenes and tumor suppressors. Further, we review strategies aimed at targeting PDK to halt tumor growth and progression.

scholarly journals Molecular interaction studies on ellagic acid for its anticancer potential targeting pyruvate dehydrogenase kinase 3

RSC Advances ◽  
2019 ◽  
Vol 9 (40) ◽  
pp. 23302-23315 ◽  
Author(s):  
Rashmi Dahiya ◽  
Taj Mohammad ◽  
Preeti Gupta ◽  
Anzarul Haque ◽  
Mohamed F. Alajmi ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Ellagic Acid ◽  
Molecular Interaction ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Reversible Phosphorylation ◽  
Interaction Studies ◽  
Metabolic Switching ◽  
The Tca Cycle

PDK3 plays a central role in cancer through the reversible phosphorylation of PDC thereby blocking the entry of pyruvate into the TCA cycle. PDK3 mediated metabolic switching can be therapeutically targeted for glycolysis addicted cancers.

scholarly journals BCKDK regulates the TCA cycle through PDC to ensure embryonic development in the absence of PDK family

2020 ◽  
Author(s):  
Lia Heinemann-Yerushalmi ◽  
Lital Bentovim ◽  
Neta Felsenthal ◽  
Ron Carmel Vinestock ◽  
Nofar Michaeli ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Bioinformatic Analysis ◽  
Compensatory Mechanism ◽  
The Tca Cycle ◽  
Early Embryonic Lethality ◽  
Branched Chain ◽  
Ketoacid Dehydrogenase

AbstractPyruvate dehydrogenase kinases (PDK1-4) inhibit the TCA cycle by phosphorylating pyruvate dehydrogenase complex (PDC). Here, we show that the PDK family is dispensable for the survival of murine embryonic development and that BCKDK serves as a compensatory mechanism by inactivating PDC.First, we knocked out all fourPdkgenes one by one. Surprisingly,Pdktotal KO embryos developed and were born in expected ratios, but died by postnatal day 4 due to hypoglycemia or ketoacidosis.Finding that PDC was phosphorylated in these embryos suggested that another kinase compensates for the PDK family. Bioinformatic analysis implicated brunch chain ketoacid dehydrogenase kinase (Bckdk), a key regulator of branched chain amino acids (BCAA) catabolism. Indeed, knockout ofBckdkand thePdkfamily led to loss of PDC phosphorylation, increment in PDC activity, elevation of Pyruvate flux into the TCA and early embryonic lethality. These findings reveal a new regulatory crosstalk hardwiring BCAA and glucose catabolic pathways, which feed the TCA cycle.

ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4

2013 ◽  
Vol 304 (8) ◽  
pp. H1103-H1113 ◽  
Author(s):  
Jun Mori ◽  
Osama Abo Alrob ◽  
Cory S. Wagg ◽  
Robert A. Harris ◽  
Gary D. Lopaschuk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Critical Role ◽  
Pyruvate Dehydrogenase Kinase ◽  
Ang Ii ◽  
Oxidation Rates

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.

Increased glutaminolytic flux and activation of mitochondrial metabolism by BCL2 hyperactivity in lymphoma

2017 ◽  
Author(s):  
Kirandeep Kaur ◽  
Simar Singh ◽  
Helma Zecena ◽  
Laurent Dejean ◽  
Fabian V. Filipp
Keyword(s):  
B Cell ◽  
Pyruvate Dehydrogenase ◽  
Metabolic Networks ◽  
Metabolic Flux ◽  
Cell Lymphoma ◽  
Pyruvate Dehydrogenase Complex ◽  
B Cell Lymphoma ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Phenotype

AbstractB-cell lymphoma 2 (BCL2) is an important apoptosis regulator during developmental and pathological states, and its overexpression is a key feature of several malignancies. Genomic data from The Cancer Genome Atlas (TCGA) reveals significant somatic copy number amplification, overexpression, and/or elevated protein activity of BCL2 in 50 % of diffuse large B-cell lymphoma (DLBC) patients. While its canonical role in mitochondria-directed apoptosis is well established, the effect of BCL2 on transcriptional and metabolic networks remains elusive. Using an established lymphocytic pro-B-cell line overexpressing BCL2, we identified dysregulated transcriptional and metabolic networks by transcriptomic profiling arrays. Elevated BCL2 levels affect transcription factor complexes and mitogenic programs of NF-κB/REL, HIF1A/ARNT, AP1, E2F, and STAT factors. Using stable isotope-assisted metabolic flux measurements we quantify that elevated BCL2 expression increases carbon utilization boosting cellular proliferation. Tumorigenic overexpression of BCL2 significantly increases glycolytic flux, glutaminolysis, and anaplerotic flux into the TCA cycle. At the same time, the mitochondrial acetyl-CoA pool is separated from the glycolytic one by inactivating the pyruvate dehydrogenase complex via transcriptional regulation of pyruvate dehydrogenase kinase (PDK3). As compensatory fuel, mitochondrial TCA cycle metabolism is supported by asparagine synthase (ASNS) and oxidative glutaminolysis creating targets for small molecule inhibition of glutaminase. Lymphoma cells overexpressing BCL2 contained more mitochondrial mass and were more sensitive to L-glutamine deprivation and glutaminase inhibition. Cells overexpressing a mutant BCL2 G145E, which is incapable of binding BH domain members, failed to increase proliferation, glycolysis, or glutaminolysis. Taken together, the oncogene BCL2 has the ability to ramp up a metabolic phenotype supporting proliferation independent of its anti-apoptotic role. The cellular model of BCL2 activation supports NF-KB-positive subtypes of DLBC and identifies metabolic bottlenecks with dependency on anaplerotic flux as an actionable BCL2 effector network in cancer.

scholarly journals Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation

2006 ◽  
Vol 397 (3) ◽  
pp. 417-425 ◽  
Author(s):  
Nam Ho Jeoung ◽  
Pengfei Wu ◽  
Mandar A. Joshi ◽  
Jerzy Jaskiewicz ◽  
Cheryl B. Bock ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Glucose Homoeostasis ◽  
Pyruvate Oxidation ◽  
Activity State ◽  
Reduced Rate

The PDC (pyruvate dehydrogenase complex) is strongly inhibited by phosphorylation during starvation to conserve substrates for gluconeogenesis. The role of PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) in regulation of PDC by this mechanism was investigated with PDHK4−/− mice (homozygous PDHK4 knockout mice). Starvation lowers blood glucose more in mice lacking PDHK4 than in wild-type mice. The activity state of PDC (percentage dephosphorylated and active) is greater in kidney, gastrocnemius muscle, diaphragm and heart but not in the liver of starved PDHK4−/− mice. Intermediates of the gluconeogenic pathway are lower in concentration in the liver of starved PDHK4−/− mice, consistent with a lower rate of gluconeogenesis due to a substrate supply limitation. The concentration of gluconeogenic substrates is lower in the blood of starved PDHK4−/− mice, consistent with reduced formation in peripheral tissues. Isolated diaphragms from starved PDHK4−/− mice accumulate less lactate and pyruvate because of a faster rate of pyruvate oxidation and a reduced rate of glycolysis. BCAAs (branched chain amino acids) are higher in the blood in starved PDHK4−/− mice, consistent with lower blood alanine levels and the importance of BCAAs as a source of amino groups for alanine formation. Non-esterified fatty acids are also elevated more in the blood of starved PDHK4−/− mice, consistent with lower rates of fatty acid oxidation due to increased rates of glucose and pyruvate oxidation due to greater PDC activity. Up-regulation of PDHK4 in tissues other than the liver is clearly important during starvation for regulation of PDC activity and glucose homoeostasis.

scholarly journals Pyruvate dehydrogenase kinases (PDKs): an overview toward clinical applications

2021 ◽  
Vol 41 (4) ◽  
Author(s):  
Xiuxiu Wang ◽  
Xiaoyue Shen ◽  
Yuting Yan ◽  
Hongmin Li
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Metabolic Diseases ◽  
Tricarboxylic Acid Cycle ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Future Research ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Atp Generation

Abstract Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs.

Sign in / Sign up

Export Citation Format

Share Document