miR‐128‐3p contributes to mitochondrial dysfunction and induces apoptosis in glioma cells via targeting pyruvate dehydrogenase kinase 1

IUBMB Life ◽  
2019 ◽  
Vol 72 (3) ◽  
pp. 465-475 ◽  
Author(s):  
Changda Qu ◽  
Chang Yan ◽  
Weifan Cao ◽  
Fangqin Li ◽  
Yewei Qu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Pyruvate Dehydrogenase ◽  
Glioma Cells ◽  
Pyruvate Dehydrogenase Kinase ◽  
Pyruvate Dehydrogenase Kinase 1

scholarly journals Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 325
Author(s):  
Carolina Venturoli ◽  
Ilaria Piga ◽  
Matteo Curtarello ◽  
Martina Verza ◽  
Giovanni Esposito ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Metabolic Pathways ◽  
Negative Impact ◽  
Digital Pathology ◽  
Pyruvate Dehydrogenase Kinase ◽  
Ovarian Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase 1

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.

scholarly journals MiR-138 protects cardiac cells against hypoxia through modulation of glucose metabolism by targetting pyruvate dehydrogenase kinase 1

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Hang Zhu ◽  
Hao Xue ◽  
Qin-Hua Jin ◽  
Jun Guo ◽  
Yun-Dai Chen
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Mitochondrial Respiration ◽  
Cardiac Cells ◽  
Pyruvate Dehydrogenase Kinase ◽  
Cellular Respiration ◽  
Small Noncoding Rnas ◽  
Direct Binding ◽  
Inhibition Of Glycolysis ◽  
Pyruvate Dehydrogenase Kinase 1 ◽  
Novel Therapeutic Strategies

Dysfunction of cardiac cells under hypoxia has been identified as an essential event leading to myocytes functional failure. MiRNAs are importantly regulatory small-noncoding RNAs that negatively regulate gene expression through the direct binding of 3′-UTR region of their target mRNAs. Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under pathological conditions.Pyruvate dehydrogenase kinase 1 (PDK1) is a kinase which phosphorylates pyruvate dehydrogenase to inactivate it, leading to elevated anaerobic glycolysis and decreased cellular respiration. In the present study, we report that miR-138 expressions were significantly suppressed under long exposure to hypoxia. In addition, overexpression of miR-138 protects human cardiac cells against hypoxia. We observed miR-138 inhibits glycolysis but promotes mitochondrial respiration through directly targetting PDK1. Moreover, we demonstrate that hypoxia induces cardiac cell death through increased glycolysis and decreased mitochondrial respiration. Inhibition of glycolysis by either glycolysis inhibitor or knockdown glycolysis enzymes, Glucose transportor 1 (Glut1) or PDK1 contributes to cardiac cells’ survival. The cell sentivity to hypoxia was recovered when the PDK1 level was restored in miR-138 overexpressing cardiac cells. The present study leads to the intervention of novel therapeutic strategies against cardiac cells dysfunction during surgery or ischemia.

scholarly journals Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1

2007 ◽  
Vol 27 (21) ◽  
pp. 7381-7393 ◽  
Author(s):  
Jung-whan Kim ◽  
Ping Gao ◽  
Yen-Chun Liu ◽  
Gregg L. Semenza ◽  
Chi V. Dang
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Pyruvate Dehydrogenase ◽  
Hypoxia Inducible Factor ◽  
Pyruvate Dehydrogenase Kinase ◽  
Vascular Endothelial ◽  
Hexokinase 2 ◽  
Pyruvate Dehydrogenase Kinase 1 ◽  
Cell Growth And Proliferation ◽  
Endothelial Growth Factor

ABSTRACT Hypoxia is a pervasive microenvironmental factor that affects normal development as well as tumor progression. In most normal cells, hypoxia stabilizes hypoxia-inducible transcription factors (HIFs), particularly HIF-1, which activates genes involved in anaerobic metabolism and angiogenesis. As hypoxia signals a cellular deprivation state, HIF-1 has also been reported to counter the activity of MYC, which encodes a transcription factor that drives cell growth and proliferation. Since many human cancers express dysregulated MYC, we sought to determine whether HIF-1 would in fact collaborate with dysregulated MYC rather countering its function. Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. We also found the collaborative induction of vascular endothelial growth factor (VEGF) by HIF-1 and dysregulated c-Myc. This study reports the previously unsuspected collaboration between HIF-1 and dysregulated MYC and thereby provides additional insights into the regulation of VEGF and the Warburg effect, which describes the propensity for cancer cells to convert glucose to lactate.

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