Dataset Information

Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma.

ABSTRACT: BACKGROUND:Hepatocellular Carcinoma (HCC) is the third most common cause of cancer related death worldwide. Adequate treatment options for patients with advanced HCC are currently limited. MATERIALS AND METHODS:We studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids. RESULTS:FH535 and Y3 disrupted mitochondrial redox control in HCC cells that resulted from uncoupling mechanisms that increased proton leakage and decreased ATP production leading to apoptosis. The uncoupling effects of the sulfonamides in HCC cells were supported by the loss of activity of the methylated analogs. The accumulation of ROS significantly contributed to cell damage after the impaired autophagic machinery. These sulfonamides, FH535 and Y3, targeted glutamine and fatty acid metabolism and caused HCC cell reprograming towards the preferential use of glucose and the glycolytic pathway. CONCLUSIONS:FH535, and Y3, demonstrated potent anti-HCC activity by targeting OXPHOS, increasing dangerous levels of ROS and reducing ATP production. These sulfonamides target glutamine and FA metabolic pathways significantly increasing the cellular dependency on glycolysis.

SUBMITTER: Turcios L

PROVIDER: S-EPMC7415405 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma.

Turcios Lilia L Marti Francesc F Watt David S DS Kril Lilia M LM Khurana Aman A Chapelin Fanny F Liu Chunming C Zwischenberger Joseph B JB Evers B Mark BM Gedaly Roberto R

Oncotarget 20200804 31

<h4>Background</h4>Hepatocellular Carcinoma (HCC) is the third most common cause of cancer related death worldwide. Adequate treatment options for patients with advanced HCC are currently limited.<h4>Materials and methods</h4>We studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids.<h4>Results</h4>FH535 and Y3 disrupted mitochondrial redox control i ...[more]

PMID: 32821346

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Project description:Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, reflecting the need for a better understanding of hepatocarcinogenesis. In this study, we examined the genome-wide expression profiles of both miRNAs and mRNAs from paired tumor and adjacent non-tumor tissues from a cohort of 96 HCC patients in Hong Kong where hepatitis B virus (HBV) is endemic. The comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that it is an important regulator for normal mitochondrial metabolism. A decreased level of miR-122 leads to an increase in expression of miR-122 seed-matched genes, a loss of mitochondrial metabolic function, and a decrease in the expression of many miR-122 secondary targets. These secondary targets are prognostic markers for HCC patients. Transcriptome profiling data from an additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. To test the HCC findings in normal mouse liver, we used an antagomir against miR-122 and identified altered gene expression profiling by microarray analysis in mouse in vivo experiments. The mouse data recapitulated the human HCC findings. Our anti-miR122 data further provided a direct link between increases in the mRNA levels of miR-122 controlled genes and impairments of mitochondrial metabolism. In summary, we find miR-122 loss may be detrimental to mitochondrial-related metabolisms in sustaining critical liver function and contribute to the morbidity and mortality of liver cancer patients. Mouse liver profiling: In one treatment regimen, four animals were given four doses of 100mg ASO/kg body weight, administered every other day, and sacrificed one day after the last dose. Four animals treated for four weeks were treated twice weekly with 50mg ASO/kg body weight, and sacrificed two days after the last dose. Mice were sacrificed in the morning, and liver was removed for further analysis. Samples from oligonucleotide-treated mice were referenced against samples from saline-treated mice in fluor-reversed pairs. Human liver profiling: For human HCC patient samples, 192 samples -- 96 resected tumor and 96 adjacent non-tumor liver tissues -- were collected from 96 patients who had undergone hepatectomy for curative treatment of HCC at Queen Mary Hospital, Pokfulam, Hong Kong between 1990 and 2007. Informed consents were obtained from patients regarding the use of the liver specimens for research. Samples were hybridized to Affymetrix arrays for mRNA profiling and were analyzed by quantitative PCR for microRNA profiling.

Dataset Information

Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma.

Publications

Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma.

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