Aberrant ketolysis fuels hepatocellular cancer progression

Galluzzi, Lorenzo; Kroemer, Guido

doi:10.1038/cr.2016.110

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…Oxctl was upregulated on day 2 and 4. Oxctl was upregulated and induced ATP production from ketone bodies when hepatocellular carcinoma were deprived of serum ( Galluzzi and Kroemer, 2016 ). Increase of Oxctl during H 2 S exposure may indicate a switch from glucose metabolism to alternative sources of ATP production in IC of mice exposed acutely to H 2 S. Further studies are warranted to check whether Coxy6c, mt-Co2, and Oxctl are the bona fide targets of H 2 S toxicity.…”

Section: Discussionmentioning

confidence: 99%

Broad spectrum proteomics analysis of the inferior colliculus following acute hydrogen sulfide exposure

Kim

Anantharam

Hoffmann

et al. 2018

Toxicology and Applied Pharmacology

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Acute exposure to high concentrations of HS causes severe brain injury and long-term neurological disorders, but the mechanisms involved are not known. To better understand the cellular and molecular mechanisms involved in acute HS-induced neurodegeneration we used a broad-spectrum proteomic analysis approach to identify key molecules and molecular pathways involved in the pathogenesis of acute HS-induced neurotoxicity and neurodegeneration. Mice were subjected to acute inhalation exposure of up to750 ppm of HS. HS induced behavioral deficits and severe lesions including hemorrhage in the inferior colliculus (IC). The IC was microdissected for proteomic analysis. Tandem mass tags (TMT) liquid chromatography mass spectrometry (LC-MS/MS)-based quantitative proteomics was applied for protein identification and quantitation. LC-MS/MS identified 598, 562, and 546 altered proteomic changes at 2 h, and on days 2 and 4 post-HS exposure, respectively. Of these, 77 proteomic changes were statistically significant at any of the 3 time points. Mass spectrometry data were subjected to Perseus 1.5.5.3 statistical analysis, and gene ontology heat map clustering. Expressions of several key molecules were verified to confirm HS-dependent proteomics changes. Webgestalt pathway overrepresentation enrichment analysis with Panther engine revealed HS exposure disrupted several biological processes including metabotropic glutamate receptor group 1 and inflammation mediated by chemokine and cytokine signaling pathways among others. Further analysis showed that energy metabolism, integrity of blood-brain barrier, hypoxic, and oxidative stress signaling pathways were also implicated. Collectively, this broad-spectrum proteomics data has provided important clues to follow up in future studies to further elucidate mechanisms of HS-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Broad spectrum proteomics analysis of the inferior colliculus following acute hydrogen sulfide exposure

Kim

Anantharam

Hoffmann

et al. 2018

Toxicology and Applied Pharmacology

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“…On the other hand, throughout ketolysis, acetoacetate and β-HB are used as an energy source by the mitochondria of several extrahepatic tissues [148,154]. B-HB is transformed to acetoacetate by the BDH1, and this last product is turned into acetoacetyl-CoA by the enzyme beta-ketoacyl-CoA transferase (OXCT1 or SCOT).…”

Section: Ketones and Mitochondrial Signalingmentioning

confidence: 99%

Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

et al. 2022

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Mitochondria are important organelles that act as a primary site to produce reactive oxygen species (ROS). Additionally, mitochondria play a pivotal role in the regulation of Ca2+ signaling, fatty acid oxidation, and ketone synthesis. Dysfunction of these signaling molecules leads to the development of pulmonary hypertension (PH), atherosclerosis, and other vascular diseases. Features of PH include vasoconstriction and pulmonary artery (PA) remodeling, which can result from abnormal proliferation, apoptosis, and migration of PA smooth muscle cells (PASMCs). These responses are mediated by increased Rieske iron–sulfur protein (RISP)-dependent mitochondrial ROS production and increased mitochondrial Ca2+ levels. Mitochondrial ROS and Ca2+ can both synergistically activate nuclear factor κB (NF-κB) to trigger inflammatory responses leading to PH, right ventricular failure, and death. Evidence suggests that increased mitochondrial ROS and Ca2+ signaling leads to abnormal synthesis of ketones, which play a critical role in the development of PH. In this review, we discuss some of the recent findings on the important interactive role and molecular mechanisms of mitochondrial ROS and Ca2+ in the development and progression of PH. We also address the contributions of NF-κB-dependent inflammatory responses and ketone-mediated oxidative stress due to abnormal regulation of mitochondrial ROS and Ca2+ signaling in PH.

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“…[8] Interestingly, twenty hepatocellular lesions displayed increased levels of OXCT1 (mRNA) and OXCT1 (protein). Interestingly, an aberrant ketolysis pathway was recently reported for continuous energy supply in cancer cells [9].…”

Section: Ketolysis In Cancer Cellsmentioning

confidence: 99%

Dichloroacetate is Promising for Treating Hematological Malignancy through Inhibiting Ketone Bodies Oxidation: towards Better Understanding of Its Anticancer Mechanisms

Ayat¹

2018

AJCP

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Dichloroacetate (DCA) is a promising anticancer drug that exerts potent anticancer effects in many clinical oncology studies. On biochemical and pharmacological bases, this article aims at gaining a better understanding of DCA anticancer effects. Ketone bodies oxidation (ketolysis) is an important source of energy to many cancer cells. Here, it is proved that DCA antagonizes acetoacetate and targets cancer cells' energetics through inhibiting ketolysis as novel evidence-based anticancer mechanisms. DCA was reported to inhibit oxidation of both ketone bodies (acetoacetate and β-hydroxybutyrate) in addition to palmitate. Acetoacetate diverted pyruvate metabolism from pyruvate dehydrogenase (PDH) to pyruvate carboxylation while DCA increased the oxidation of glucose through PDH. This suggests an antagonism between DCA and ketone bodies. Moreover, DCA was reported to inhibit β-hydroxybutyrate uptake by the extra-splanchnic tissues and decrease the clearance of ketone bodies. That may be explained by structural antagonism between DCA and ketone bodies leading to a competitive uptake at target tissues i.e. DCA may competitively antagonize ketone bodies. In a previous study, DCA infusion in starved rats caused a significant decrease in blood glucose, plasma insulin, blood lactate and pyruvate concentrations but significantly increased concentrations of ketone bodies (β-hydroxybutyrate and acetoacetate) (Blackshear et al., 1974). Based on that, DCA inhibits ketone bodies utilization for energy production. In conclusion, DCA enhances anticancer immunity, targets anaerobic cancer cell populations (via targeting Warburg effect) and targets aerobic cancer cell populations through targeting mitochondrial energy generating pathways e.g. ketolysis.

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Aberrant ketolysis fuels hepatocellular cancer progression

Cited by 5 publications

References 11 publications

Broad spectrum proteomics analysis of the inferior colliculus following acute hydrogen sulfide exposure

Broad spectrum proteomics analysis of the inferior colliculus following acute hydrogen sulfide exposure

Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

Dichloroacetate is Promising for Treating Hematological Malignancy through Inhibiting Ketone Bodies Oxidation: towards Better Understanding of Its Anticancer Mechanisms

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