PDF(Pubmed)
Abstract：
Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H2O2 or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis.
摘要：
细胞色素c(Cytc)对线粒体呼吸和细胞凋亡都很重要,两者在癌细胞中都发生了改变，这些癌细胞转变为Warburg代谢并设法逃避凋亡。我们早先报道了Cytc的赖氨酸53(K53)在前列腺癌中被乙酰化。已知K53在哺乳动物中是保守的,其对于结合细胞色素c氧化酶和凋亡蛋白酶活化因子-1(Apaf-1)是必需的。在这里，我们通过在细胞色素c双敲除细胞中表达乙酰模拟物K53Q来报道这种乙酰化对细胞色素c主要功能的影响。分析的其他细胞色素c变体是野生型，K53R作为保持正电荷的对照，K53I,存在于一些非哺乳动物物种中。表达K53Q细胞色素c的完整细胞显示线粒体呼吸降低了49％，糖酵解活性随之增加（Warburg效应）。此外，线粒体膜电位下降，与H2O2或星形孢菌素攻击后基础线粒体超氧化物水平显着降低和细胞死亡减少相关。为了测试癌症侵袭性和侵袭性的标志物，细胞在3D球体培养中生长。与WT相比，K53Q细胞色素c表达细胞显示出明显增加的突起，表明侵入性增加。我们认为细胞色素c的K53乙酰化是介导前列腺癌代谢重编程和逃避凋亡的适应性反应。这是癌症的两个标志，从而更好地促进肿瘤的生存和转移。
