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

Lilia Turcios; Francesc Marti; David S. Watt; Lilia M. Kril; Aman Khurana; Fanny Chapelin; Chunming Liu; Joseph B. Zwischenberger; B. Mark Evers; Roberto Gedaly

doi:10.18632/oncotarget.27680

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

Lilia Turcios, Francesc Marti, David S. Watt, Lilia M. Kril, Aman Khurana, Fanny Chapelin, Chunming Liu, Joseph B. Zwischenberger, B. Mark Evers, Roberto Gedaly

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English
Pages (from-to)	3013-3024
Number of pages	12
Journal	Oncotarget
Volume	11
Issue number	31
DOIs	https://doi.org/10.18632/oncotarget.27680
State	Published - Aug 1 2020

Bibliographical note

Funding Information:
This research was supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). The UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30CA177558) to the University of Kentucky Markey Cancer Center. This research was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1TR001998 to R.G. and F.M. The Redox Metabolism Shared Resource (RMSR) and the University of Kentucky Flow Cytometry and Immune Monitoring (FCIM) core facilities received support from the National Cancer Institute (NCI) NIH Cancer Center Support Grant P30CA177558 awarded to the University of Kentucky Markey Cancer Center. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
Copyright: © Turcios et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

Glutamine metabolism
Hepatocellular carcinoma
Mitochondria
Proton uncouplers
Wnt/β-catenin pathway

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.27680

Cite this

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title = "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.",

keywords = "Glutamine metabolism, Hepatocellular carcinoma, Mitochondria, Proton uncouplers, Wnt/β-catenin pathway",

author = "Lilia Turcios and Francesc Marti and Watt, {David S.} and Kril, {Lilia M.} and Aman Khurana and Fanny Chapelin and Chunming Liu and Zwischenberger, {Joseph B.} and {Mark Evers}, B. and Roberto Gedaly",

note = "Funding Information: This research was supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). The UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30CA177558) to the University of Kentucky Markey Cancer Center. This research was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1TR001998 to R.G. and F.M. The Redox Metabolism Shared Resource (RMSR) and the University of Kentucky Flow Cytometry and Immune Monitoring (FCIM) core facilities received support from the National Cancer Institute (NCI) NIH Cancer Center Support Grant P30CA177558 awarded to the University of Kentucky Markey Cancer Center. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: Copyright: {\textcopyright} Turcios et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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doi = "10.18632/oncotarget.27680",

language = "English",

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AU - Turcios, Lilia

AU - Marti, Francesc

AU - Watt, David S.

AU - Kril, Lilia M.

AU - Khurana, Aman

AU - Chapelin, Fanny

AU - Liu, Chunming

AU - Zwischenberger, Joseph B.

AU - Mark Evers, B.

AU - Gedaly, Roberto

N1 - Funding Information: This research was supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). The UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30CA177558) to the University of Kentucky Markey Cancer Center. This research was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1TR001998 to R.G. and F.M. The Redox Metabolism Shared Resource (RMSR) and the University of Kentucky Flow Cytometry and Immune Monitoring (FCIM) core facilities received support from the National Cancer Institute (NCI) NIH Cancer Center Support Grant P30CA177558 awarded to the University of Kentucky Markey Cancer Center. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: Copyright: © Turcios et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

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KW - Hepatocellular carcinoma

KW - Mitochondria

KW - Proton uncouplers

KW - Wnt/β-catenin pathway

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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