Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase

Golias, Tereza; Kery, Martin; Radenkovic, Silvia; Papandreou, Ioanna

doi:10.1002/ijc.31812

Cited by 60 publications

(56 citation statements)

References 153 publications

(176 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acetyl-CoA is produced from the end product of glycolysis, pyruvate, through a process called “pyruvate decarboxylation” or “pyruvate oxidation”. The process is mediated by the pyruvate dehydrogenase (PDH) complex, whose first component enzyme is pyruvate dehydrogenase E1α (PDH-E1α) [52,53]. Because PDH-E1α activity is suppressed through its phosphorylation by pyruvate dehydrogenase kinase 1 (PDK1) and HIF-1 is responsible for the expression of PDK1, activation of HIF-1 leads to a decrease in acetyl-CoA levels and inactivation of the TCA cycle [54,55].…”

Section: Functions Of Hif-1 In the Warburg Effect: Switch From Mitmentioning

confidence: 99%

HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

Nagao

Kobayashi

Koyasu

et al. 2019

IJMS

344

226

View full text Add to dashboard Cite

Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.

show abstract

Section: Functions Of Hif-1 In the Warburg Effect: Switch From Mitmentioning

confidence: 99%

HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

Nagao

Kobayashi

Koyasu

et al. 2019

IJMS

344

226

View full text Add to dashboard Cite

show abstract

“…It is well known that, in many types of cancers, PDKs, especially PDK1, are overexpressed and/or its activity is increased by post-translational modifications [ 4 , 5 , 6 ]. In addition, PDK1 is highly expressed in non-small cell lung cancer (NSCLC), and its overexpression is significantly correlated with poor prognosis in human NSCLC tissues [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Kwak

Han

et al. 2020

IJMS

View full text Add to dashboard Cite

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

show abstract

“…Pyruvate dehydrogenase (PDH) is a multienzyme complex that regulates carbohydrate and fat metabolism and catalyzes the conversion of pyruvate into acetyl‐CoA by irreversible decarboxylation. Acetyl‐CoA plays an important role in many biological reactions . PDHA1, as the major component of PDH, can be phosphorylated and inactivated by PDK1 .…”

Section: Introductionmentioning

confidence: 99%

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

Yang

Zhou

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetylase also known as Sirtuin‐3 (SIRT3) has been shown to regulate cellular metabolism in various cancers dynamically. However, the biological function of SIRT3 in CCA remains unclear. In this study, bioinformatics analyses were performed to identify the differentially expressed genes and pathways enriched. CCA samples were collected for immunohistochemical analysis. Three human CCA cell lines (HuCCT1, RBE, and HCCC9810) were used to explore the molecular mechanism of SIRT3 regulation of metabolic reprogramming and malignant behavior in CCA. A CCA xenograft model was then established for further validation in vivo. The data showed that SIRT3 expression was decreased and glycolysis was enhanced in CCA. Similar metabolic reprogramming was also observed in SIRT3 knockout mice. Furthermore, we demonstrated that SIRT3 could play an anti‐Warburg effect by inhibiting the hypoxia‐inducible factor‐1α (HIF1α)/pyruvate dehydrogenase kinase 1 (PDK1)/pyruvate dehydrogenase (PDHA1) pathway in CCA cells. CCA cell proliferation and apoptosis were regulated by SIRT3‐mediated metabolic reprogramming. These findings were further confirmed in CCA clinical samples and the xenograft model. Collectively, this study suggests that in the inhibition of CCA progression, SIRT3 acts through an anti‐Warburg effect on the downstream pathway HIF1α/PDK1/PDHA1.

show abstract

Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase

Cited by 60 publications

References 153 publications

HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

Contact Info

Product

Resources

About