Dual role of mitochondrial reactive oxygen species in hypoxia signaling:: Activation of nuclear factor-κB via c-SRC- and oxidant-dependent cell death
Dual role of mitochondrial reactive oxygen species in hypoxia signaling:: Activation of nuclear factor-κB via c-SRC- and oxidant-dependent cell death
复制标题
DOI：
10.1158/0008-5472.can-07-0515
复制
发表时间：
2007-08-01
期刊：
影响因子：
11.2
通讯作者：
Fernandez-Checa, Jose C.
中科院分区：
文献类型：
--
作者：
Lluis, Josep M.;Buricchi, Francesca;Fernandez-Checa, Jose C.
缺氧是实体瘤发展的一个显着特征，已知会刺激线粒体 ROS (mROS)，进而激活缺氧诱导的转录因子 kappa B 和核因子 kappa B (NF-kappa B)。由于 NF-kappa B 在致癌作用中发挥着核心作用，我们研究了 mROS 介导的 NF-kappa B 激活机制以及线粒体还原型谷胱甘肽 (mGSH) 耗尽后缺氧期间癌细胞的命运。缺氧在肝癌 (HepG2、H35)、神经母细胞瘤 (SH-SY5Y) 和结肠癌 (DLD-1) 细胞中产生 mROS，导致缺氧诱导的转录因子 1 α 依赖性基因表达和 c-Src 激活，而在表达氧化还原不敏感的 c-Src 突变体 (C487A) 的细胞中，c-Src 激活被阻止。 c-Src 刺激激活 NF-kappa B，但由于 I kappa B-α 酪氨酸磷酸化被鱼藤酮/TTFA 或 c-Src 拮抗作用抑制，因此 I kappa B-α 没有降解。 c-Src-NF-kappa B 信号传导有助于缺氧期间细胞的存活，因为小干扰 RNA 敏感的 HepG2 细胞抑制 c-Src 或 p65 下调，从而导致缺氧诱导的细胞死亡。此外，选择性 mGSH 消耗导致缺氧加速和增强 mROS 生成，从而杀死 SH-SY5Y 和 DLD-1 细胞，而不会禁用 c-Src-NF-kappa B 途径。因此，尽管 mROS 通过 c-Src 激活 NF-kappa B 来促进细胞存活，但 mROS 过度生成可用于使癌细胞对缺氧敏感。
Hypoxia is a prominent feature of solid tumor development and is known to stimulate mitochondrial ROS (mROS), which, in turn, can activate hypoxia-inducible transcription factorto- and nuclear factor-kappa B (NF-kappa B). Because NF-kappa B plays a central role in carcinogenesis, we examined the mechanism of mROS-mediated NF-kappa B activation and the fate of cancer cells during hypoxia after mitochondrial reduced glutathione (mGSH) depletion. Hypoxia generated mROS in hepatoma (HepG2, H35), neuroblastoma (SH-SY5Y), and colon carcinoma (DLD-1) cells, leading to hypoxia-inducible transcription factor-1 alpha-dependent gene expression and c-Src activation that was prevented in cells expressing a redox-insensitive c-Src mutant (C487A). c-Src stimulation activated NF-kappa B without I kappa B-alpha degradation due to I kappa B-alpha tyrosine phosphorylation that was inhibited by rotenone/TTFA or c-Src antagonism. The c-Src-NF-kappa B signaling contributed to the survival of cells during hypoxia as c-Src inhibition or p65 down-regulation by small interfering RNA-sensitized HepG2 cells to hypoxia-induced cell death. Moreover, selective mGSH depletion resulted in an accelerated and enhanced mROS generation by hypoxia that killed SH-SY5Y and DLD-1 cells without disabling the c-Src-NF-kappa B pathway. Thus, although mROS promote cell survival by NF-kappa B activation via c-Src, mROS overgeneration may be exploited to sensitize cancer cells to hypoxia.