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

被引：65

作者：

Baulies, Anna ^{[1
,2
,3
,4
,10
]}

Montero, Joan ^{[1
,2
,3
,4
,11
]}

Matias, Nuria ^{[1
,2
,3
,4
]}

Insausti, Naroa ^{[1
,2
,3
,4
]}

Terrones, Oihana ^{[5
]}

Basanez, Gorka ^{[5
]}

Vallejo, Carmen ^{[1
,2
,3
,4
]}

Conde de La Rosa, Laura ^{[1
,2
,3
,4
]}

Martinez, Laura ^{[1
,2
,3
,4
]}

Robles, David ^{[1
,2
,3
,4
]}

Morales, Albert ^{[1
]}

Abian, Joaquin ^{[6
]}

Carrascal, Montserrat ^{[6
]}

Machida, Keigo ^{[5
]}

Kumar, Dinesh B. U. ^{[7
]}

Tsukamoto, Hidekazu ^{[7
,8
]}

Kaplowitz, Neil ^{[9
]}

Garcia-Ruiz, Carmen ^{[1
,2
,3
,4
,7
,9
]}

Fernandez-Checa, Jose C. ^{[1
,2
,3
,4
,7
,9
]}

机构：

[1] CSIC, Inst Invest Biomed Barcelona, Dept Cell Death & Proliferat, Barcelona 08036, Spain

[2] IDIBAPS, Liver Unit, Barcelona, Spain

[3] IDIBAPS, Hosp Clin & Prov, Barcelona, Spain

[4] Ctr Invest Biomed Red CIBERehd, Barcelona, Spain

[5] Univ Basque Country, Euskal Herriko Unibertsitatea, Ctr Mixto Consejo Super Invest Cient, Unidad Biofis, E-48080 Bilbao, Spain

[6] IIBB CSIC, CSIC UAB Prote Lab, Barcelona 08036, Spain

[7] Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA

[8] Dept Vet Affairs Greater Los Angeles Healthcare S, Los Angeles, CA USA

[9] USC, Keck Sch Med, Res Ctr Liver Dis, Los Angeles, CA USA

[10] Francis Crick Inst, London, England

[11] Harvard Med Sch, Bringham & Womens Hosp, Med Oncol Dept, Dana Farber Canc Inst, Boston, MA USA

来源：

REDOX BIOLOGY | 2018年 / 14卷

关键词：

Cholesterol; Hepatocellular carcinoma; Mitochondria; Small solute carriers; Hypoxia; GLUTATHIONE TRANSPORT; OXIDATIVE STRESS; KAPPA-B; CELLS; ROS; CONTRIBUTES; RESPIRATION; ACTIVATION; DEPLETION; MEMBRANE;

D O I：

10.1016/j.redox.2017.08.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Box 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.

引用

页码：164 / 177

页数：14

共 51 条

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