Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, 08036 Barcelona, Spain; Liver Unit and Hospital Clínic i Provincial, IDIBAPS, and Centro de Investigación Biomédica en Red (CIBERehd), Spain.
Unidad de Biofísica (Centro Mixto Consejo Superior de Investigaciones Científicas-Universidad del País Vasco/Euskal Herriko Unibertsitatea), Universidad del País Vasco/Euskal Herriko Unibertsitatea, 48080 Bilbao, Spain.
Redox Biol. 2018 Apr;14:164-177. doi: 10.1016/j.redox.2017.08.022. Epub 2017 Sep 14.
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.
癌细胞表现出线粒体胆固醇（mt-cholesterol）积累，通过拮抗线粒体外膜（MOM）通透性增加来抵抗细胞死亡。然而，肝细胞 mt-cholesterol 负荷通过胆固醇介导的 mGSH 转运受损导致线粒体 GSH（mGSH）耗竭，促进脂肪性肝炎，这是慢性肝病的晚期阶段，发生在肝细胞癌（HCC）之前。由于 mGSH 转运尚未完全了解，SLC25A10（二羧酸载体，DIC）和 SLC25A11（2-氧戊二酸载体，OGC）已经参与 mGSH 转运，因此我们研究了它们在 HCC 中的表达和作用。出乎意料的是，HCC 细胞和 HCC 患者的肝组织中这些线粒体载体的表达模式存在差异，表现为 OGC 的选择性上调，这有助于 mGSH 的维持。OGC 而非 DIC 的 siRNA 下调会耗尽 mGSH 水平，并使 HCC 细胞对缺氧诱导的 ROS 生成和细胞死亡以及三维多细胞 HCC 球体中的细胞生长受损敏感，通过 GSH 乙酯（一种膜通透的 GSH 前体）补充 mGSH 可逆转这些效应。我们还表明，OGC 调节线粒体呼吸和糖酵解。此外，OGC 沉默促进了缺氧诱导的心磷脂过氧化，这逆转了 Bax 或 Bak 诱导的 MOM 样脂质体通透性抑制对胆固醇的抑制。遗传 OGC 敲低降低了起始肿瘤的干细胞样细胞诱导肝癌的能力。这些发现强调了 OGC 的选择性过表达是 HCC 的一种适应性机制，可在 mt-cholesterol 负荷的情况下提供足够的 mGSH 水平，并表明 OGC 可能是 HCC 治疗的新的治疗靶点。
Zotero 插件
