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

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.

• Authors: Anna Baulies, Joan Montero, Nuria Matías, Naroa Insausti, Oihana Terrones, Gorka Basañez, Carmen Vallejo, Laura Conde de La Rosa, Laura Martinez, David Robles, Albert Morales, Joaquin Abian, Montserrat Carrascal, Keigo Machida, Dinesh B U Kumar, Hidekazu Tsukamoto, Neil Kaplowitz, Carmen Garcia-Ruiz, José C Fernández-Checa
• Journal: Redox biology (Redox Biol) Vol. 14 Pg. 164-177 (04 2018) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 28942194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Dicarboxylic Acid Transporters
• Membrane Transport Proteins
• RNA, Small Interfering
• oxoglutarate translocator
• Cholesterol
• Glutathione

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cholesterol (metabolism)
• Dicarboxylic Acid Transporters (antagonists & inhibitors, genetics, metabolism)
• Glutathione (metabolism)
• Hep G2 Cells
• Humans
• Liver (metabolism, pathology)
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Membrane Transport Proteins (chemistry, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism, pathology)
• Mitochondrial Membranes (metabolism)
• Oxidative Stress
• RNA, Small Interfering (metabolism, therapeutic use)
• Rats