Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
Department of Physiology & Biochemistry, University of Malta, Msida, Malta.
Sci Rep. 2019 Apr 16;9(1):6152. doi: 10.1038/s41598-019-39489-4.
Aspirin is a widely used anti-inflammatory and antithrombotic drug also known in recent years for its promising chemopreventive antineoplastic properties, thought to be mediated in part by its ability to induce apoptotic cell death. However, the full range of mechanisms underlying aspirin's cancer-preventive properties is still elusive. In this study, we observed that aspirin impaired both the synthesis and transport of acetyl-coenzyme A (acetyl-CoA) into the mitochondria of manganese superoxide dismutase (MnSOD)-deficient Saccharomyces cerevisiae EG110 yeast cells, but not of the wild-type cells, grown aerobically in ethanol medium. This occurred at both the gene level, as indicated by microarray and qRT-PCR analyses, and at the protein level as indicated by enzyme assays. These results show that in redox-compromised MnSOD-deficient yeast cells, but not in wild-type cells, aspirin starves the mitochondria of acetyl-CoA and likely causes energy failure linked to mitochondrial damage, resulting in cell death. Since acetyl-CoA is one of the least-studied targets of aspirin in terms of the latter's propensity to prevent cancer, this work may provide further mechanistic insight into aspirin's chemopreventive behavior with respect to early stage cancer cells, which tend to have downregulated MnSOD and are also redox-compromised.
阿司匹林是一种广泛使用的抗炎和抗血栓药物，近年来也因其有希望的化学预防抗肿瘤特性而备受关注，据认为这部分是通过其诱导细胞凋亡死亡的能力介导的。然而，阿司匹林预防癌症特性的全部机制仍难以捉摸。在这项研究中，我们观察到阿司匹林损害了锰超氧化物歧化酶 (MnSOD) 缺陷酿酒酵母 EG110 酵母细胞中乙酰辅酶 A (acetyl-CoA) 进入线粒体的合成和运输，而不是在有氧条件下在乙醇培养基中生长的野生型细胞。这既发生在基因水平上，如微阵列和 qRT-PCR 分析所示，也发生在蛋白水平上，如酶测定所示。这些结果表明，在氧化还原受损的 MnSOD 缺陷酵母细胞中，但不在野生型细胞中，阿司匹林使线粒体饥饿乙酰辅酶 A，并可能导致与线粒体损伤相关的能量衰竭，导致细胞死亡。由于乙酰辅酶 A 是阿司匹林预防癌症倾向的研究最少的靶点之一，因此这项工作可能为阿司匹林对早期癌细胞的化学预防行为提供了进一步的机制见解，早期癌细胞往往下调 MnSOD 并且也氧化还原受损。
