Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation.
Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation.
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DOI：
10.1186/s40170-015-0133-5
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发表时间：
2015
影响因子：
5.9
通讯作者：
Mazure NM
中科院分区：
文献类型：
--
作者：
Brahimi-Horn MC;Giuliano S;Saland E;Lacas-Gervais S;Sheiko T;Pelletier J;Bourget I;Bost F;Féral C;Boulter E;Tauc M;Ivan M;Garmy-Susini B;Popa A;Mari B;Sarry JE;Craigen WJ;Pouysségur J;Mazure NM
线粒体不仅仅是细胞的发电站；它们决定细胞是死是活。线粒体是动态的细胞器，在环境条件下不断进行融合和裂变。我们之前的研究表明，在低氧环境（缺氧）下，细胞的线粒体会过度灌注，形成扩大或高度互联的网络，从而增强代谢效率和抗凋亡能力。线粒体的外观和代谢能力的改变已被报道在癌症中。然而，在癌症中调节线粒体动力学和代谢的确切机制尚不清楚。由于缺氧在这些异常线粒体的产生中起作用，我们质疑它是否调节线粒体功能。线粒体外膜电压依赖性阴离子通道1 （VDAC1）在调节代谢和细胞凋亡中处于中心地位。我们之前证明，VDAC1不仅在各种缺氧癌细胞中，而且在肺腺癌患者的肿瘤组织中也存在翻译后c端切割。线粒体增大和VDAC1断裂的细胞对化疗刺激的细胞死亡的抵抗力也比正常癌细胞强。对Vdac1基因敲除的小鼠胚胎成纤维细胞（MEF）的转录组分析表明，在正常缺氧条件下，不仅癌症和炎症途径发生了变化，而且缺氧诱导因子-1 （HIF-1）信号通路的激活也发生了变化。HIF-1α由于活性氧（ROS）的积累而在常氧环境下保持稳定，从而减少呼吸和糖酵解并维持基础细胞凋亡。然而，在缺氧条件下，细胞外信号调节激酶（ERK）的激活结合呼吸的维持和糖酵解的增加抵消了ROS增强的有害影响，从而使Vdac1−/−MEF在缺氧条件下比野生型MEF增殖得更好。ras转化的Vdac1−/−MEF异体移植物表现出HIF-1α和HIF-2α的稳定，血管不稳定和强烈的炎症反应。此外，hif -1靶基因和肿瘤抑制基因Cdkn2a的表达明显降低。因此，ras转化的Vdac1−/−MEF肿瘤生长速度快于野生型MEF肿瘤。肿瘤细胞中的代谢重编程可能由VDAC1通过血管不稳定和炎症调节。这些发现为了解VDAC1不仅在癌症中而且在炎症性疾病中参与线粒体功能提供了新的视角。本文的在线版本（doi:10.1186/s40170-015-0133-5）包含补充材料，可供授权用户使用。
Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells. Transcriptome analysis of mouse embryonic fibroblasts (MEF) knocked out for Vdac1 highlighted alterations in not only cancer and inflammatory pathways but also in the activation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway in normoxia. HIF-1α was stable in normoxia due to accumulation of reactive oxygen species (ROS), which decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia, activation of extracellular signal-regulated kinase (ERK) in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of enhanced ROS, thereby allowing Vdac1−/− MEF to proliferate better than wild-type MEF in hypoxia. Allografts of RAS-transformed Vdac1−/− MEF exhibited stabilization of both HIF-1α and HIF-2α, blood vessel destabilization, and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was markedly decreased. Consequently, RAS-transformed Vdac1−/− MEF tumors grew faster than wild-type MEF tumors. Metabolic reprogramming in cancer cells may be regulated by VDAC1 through vascular destabilization and inflammation. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases. The online version of this article (doi:10.1186/s40170-015-0133-5) contains supplementary material, which is available to authorized users.