Overexpression of Pyruvate Dehydrogenase E1α Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma

Sun, Jun; Li, Jingjing; Guo, Zhixian; Sun, Lu; Juan, Chenghui; Zhou, Yubing; Gu, Hongli; Yu, Yan; Hu, Qiuyue; Kan, Quancheng; Yu, Zujiang

doi:10.3727/096504018x15180451872087

Cited by 44 publications

(36 citation statements)

References 22 publications

(9 reference statements)

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“…Determination of mitochondrial viability from OCR measurements according to Seahorse Assay recommendations 65 (Fig. 4 A, Table 2 , supplementary data ST 4 ).…”

Section: Resultsmentioning

confidence: 99%

Effect of hypoxia factors gene silencing on ROS production and metabolic status of A375 malignant melanoma cells

Špaková

Rabajdová

Mičková

et al. 2021

Sci Rep

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The innate response of melanocytes to exogenous or endogenous stress stimuli like extreme pH and temperature, metabolite and oxygen deficiency or a high UV dose initiates a cellular stress response. This process activates adaptive processes to minimize the negative impact of the stressor on the pigment cell. Under physiological conditions, a non-cancer cell is directed to apoptosis if the stressor persists. However, malignant melanoma cells will survive persistent stress thanks to distinct "cancerous" signaling pathways (e.g. MEK) and transcription factors that regulate the expression of so-called "survival genes" (e.g. HIF, MITF). In this survival response of cancer cells, MEK pathway directs melanoma cells to deregulate mitochondrial metabolism, to accumulate reduced species (NADH), and to centralize metabolism in the cytosol. The aim of this work was to study the effect of gene silencing in malignant melanoma A375 cells on metabolic processes in cytosol and mitochondria. Gene silencing of HIF-1α, and miR-210 in normoxia and pseudohypoxia, and analysis of its effect on MITF-M, and PDHA1 expression. Detection of cytosolic NADH by Peredox-mCherry Assay. Detection of OCR, and ECAR using Seahorse XF96. Measurement of produced O2•− with MitoTracker Red CMXRos. 1H NMR analysis of metabolites present in cell suspension, and medium. By gene silencing of HIF-1α and miR-210 the expression of PDHA1 was upregulated while that of MITF-M was downregulated, yielding acceleration of mitochondrial respiratory activity and thus elimination of ROS. Hence, we detected a significantly reduced A375 cell viability, an increase in alanine, inositol, nucleotides, and other metabolites that together define apoptosis. Based on the results of measurements of mitochondrial resipiratory activity, ROS production, and changes in the metabolites obtained in cells under the observed conditions, we concluded that silencing of HIF-1α and miR-210 yields apoptosis and, ultimately, apoptotic cell death in A375 melanoma cells.

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“…Determination of mitochondrial viability from OCR measurements according to Seahorse Assay recommendations 65 (Fig. 4 A, Table 2 , supplementary data ST 4 ).…”

Section: Resultsmentioning

confidence: 99%

Effect of hypoxia factors gene silencing on ROS production and metabolic status of A375 malignant melanoma cells

Špaková

Rabajdová

Mičková

et al. 2021

Sci Rep

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“…This is followed by a decrease in cytoplasmic ADP and an increase in mitochondrial ATP (state 4 respiration) characteristic of the Crabtree effect ( Figure 1 ). As a consequence, a decrease of the pyruvate oxidation occurs in the mitochondrial matrix, which may also contribute to the decrease of pyruvate transport, by a specific carrier, into the mitochondrial matrix [ 26 ], the increase in pyruvate dehydrogenase kinase 1 (PDK-1) activity [ 27 , 28 ] and, at least in HCC, the overexpression of pyruvic dehydrogenase E1α (PDH-E1α) [ 29 ]. Interestingly, the protein levels of (β-F1-adenosine-triphosphatase (β-F1-ATPase; the physiological inhibitor of the H + -ATP synthase), which are reduced in human liver, kidney, colon, breast, and stomach carcinomas, was found to be correlated, in colon cancer, with both the time of cancer recurrence and patients survival [ 30 ], suggesting that the alteration of the bioenergetic function of mitochondria is a main feature of these cancer types.…”

Section: The Deregulation Of the Oxidative Metabolism In Cancermentioning

confidence: 99%

The Warburg Effect 97 Years after Its Discovery

Pascale

Calvisi

Simile

et al. 2020

Cancers

199

128

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The deregulation of the oxidative metabolism in cancer, as shown by the increased aerobic glycolysis and impaired oxidative phosphorylation (Warburg effect), is coordinated by genetic changes leading to the activation of oncogenes and the loss of oncosuppressor genes. The understanding of the metabolic deregulation of cancer cells is necessary to prevent and cure cancer. In this review, we illustrate and comment the principal metabolic and molecular variations of cancer cells, involved in their anomalous behavior, that include modifications of oxidative metabolism, the activation of oncogenes that promote glycolysis and a decrease of oxygen consumption in cancer cells, the genetic susceptibility to cancer, the molecular correlations involved in the metabolic deregulation in cancer, the defective cancer mitochondria, the relationships between the Warburg effect and tumor therapy, and recent studies that reevaluate the Warburg effect. Taken together, these observations indicate that the Warburg effect is an epiphenomenon of the transformation process essential for the development of malignancy.

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“…Sun etc. observed that the PDHA1 protein was reduced in HCC specimens by immunohistochemistry and Western blot, which was significantly associated with poor overall survival [73]. At the same time, mitochondrial OXPHOS was enhanced accompanied with higher ATP.…”

Section: Treatment Strategies For Hcc Based Onmentioning

confidence: 90%

Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

Chen

Liu

et al. 2021

Journal of Nanomaterials

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Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer death worldwide. The incidence of HCC accounts for more than 90% of primary HCC. Like most solid malignancies, the occurrence and development of HCC are closely related to the Warburg effect. The Warburg effect of HCC is mainly manifested as increased glucose uptake by HCC cells, increased glycolysis, restricted mitochondrial oxidative phosphorylation, increased pentose phosphate pathway in HCC cells, and increased glutamine decomposition. As the contribution of glycolysis to the total ATP of tumor cells generally does not exceed 50% to 60%, oxidative phosphorylation (OXPHOS) still makes a considerable contribution to the ATP of tumor cells. In some cases, there will be an anti-Warburg effect. HCC Warburg effect is closely related to HCC cell proliferation, apoptosis, immune escape, migration and invasion, chemotherapy resistance, and treatment failure. The mechanism of the Warburg effect in HCC is complex, involving the expression of stimulating the key glycolysis enzymes by hypoxia-inducible factor-1(HIF-1), the activation of oncogenes and the inactivation of tumor suppressor genes, the continuous activation of related signaling pathways, the participation of noncoding RNA, and the rate of metabolism gene mutation of enzyme. This article synthetically discusses the characteristics of glucose metabolism in HCC cells, the mechanism of Warburg effect, clinical significance, and corresponding treatment strategies and provides new perspectives for the prevention and treatment of HCC.

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Overexpression of Pyruvate Dehydrogenase E1α Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma

Cited by 44 publications

References 22 publications

Effect of hypoxia factors gene silencing on ROS production and metabolic status of A375 malignant melanoma cells

Effect of hypoxia factors gene silencing on ROS production and metabolic status of A375 malignant melanoma cells

The Warburg Effect 97 Years after Its Discovery

Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma

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