Institut de Génétique Moléculaire de Montpellier, Unité Mixte de Recherche 5535, Centre National de Recherche Scientifique, Montpellier, France.
J Immunol. 2010 Sep 15;185(6):3498-503. doi: 10.4049/jimmunol.1001250. Epub 2010 Aug 20.
Most cancer cells use anaerobic-like glycolysis to generate energy instead of oxidative phosphorylation. They also avoid recognition by CTLs, which occurs primarily through decreasing the level of MHC class I (MHC-I) at the cell surface. We find that the two phenomena are linked; culture conditions that force respiration in leukemia cells upregulate MHC-I transcription and protein levels at the cell surface, whereas these decrease in cells forced to perform fermentation as well as in leukemia cells lacking a functional mitochondrial respiratory chain. Forced respiration leads to increased expression of the MAPK ERK5, which activates MHC-I gene promoters, and ERK5 accumulation in mitochondria. Respiration-induced MHC-I upregulation is reversed upon short hairpin RNA-mediated ERK5 downregulation and by inactive mutants of ERK5. Moreover, short hairpin RNA for ERK5 leukemia cells do not tolerate forced respiration. Thus, the expression of ERK5 and MHC-I is linked to cell metabolism and notably diminished by the metabolic adaptations found in tumor cells.
大多数癌细胞利用类似于无氧糖酵解的方式来产生能量，而不是氧化磷酸化。它们还通过降低细胞表面 MHC Ⅰ类（MHC-I）的水平来避免被 CTL 识别。我们发现这两个现象是相关的；迫使白血病细胞进行呼吸的培养条件会上调 MHC-I 的转录和细胞表面的蛋白水平，而在被迫进行发酵的细胞以及缺乏功能性线粒体呼吸链的白血病细胞中，这些水平会降低。呼吸会导致 MAPK ERK5 的表达增加，ERK5 激活 MHC-I 基因启动子，并在线粒体中积累。通过短发夹 RNA 介导的 ERK5 下调和 ERK5 的无活性突变体，可逆转呼吸诱导的 MHC-I 上调。此外，ERK5 的短发夹 RNA 使白血病细胞无法耐受强制呼吸。因此，ERK5 和 MHC-I 的表达与细胞代谢有关，并且肿瘤细胞中发现的代谢适应性显著降低了它们的表达。
