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The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading.

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Title: The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading.
Authors: Baulies, A
Montero, J
Matías, N
Insausti, N
Terrones, O
Basañez, G
Vallejo, C
Conde de La Rosa, L
Martinez, L
Robles, D
Morales, A
Abian, J
Carrascal, M
Machida, K
Kumar, DBU
Tsukamoto, H
Kaplowitz, N
Garcia-Ruiz, C
Fernández-Checa, JC
Item Type: Journal Article
Abstract: Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment.
Issue Date: 14-Sep-2017
Date of Acceptance: 24-Aug-2017
URI: http://hdl.handle.net/10044/1/53055
DOI: https://dx.doi.org/10.1016/j.redox.2017.08.022
ISSN: 2213-2317
Publisher: Elsevier
Start Page: 164
End Page: 177
Journal / Book Title: Redox Biology
Volume: 14
Copyright Statement: © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Keywords: Cholesterol
Hepatocellular carcinoma
Hypoxia
Mitochondria
Small solute carriers
Publication Status: Published
Appears in Collections:Department of Surgery and Cancer