Madreiter-Sokolowski Corina T, Győrffy Balázs, Klec Christiane, Sokolowski Armin A, Rost Rene, Waldeck-Weiermair Markus, Malli Roland, Graier Wolfgang F
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
Oncotarget. 2017 Aug 28;8(46):80278-80285. doi: 10.18632/oncotarget.20571. eCollection 2017 Oct 6.
Cancer cells have developed unique strategies to meet their high energy demand. Therefore, they have established a setting of Ca-triggered high mitochondrial activity. But mitochondrial Ca uptake has to be strictly controlled to avoid mitochondrial Ca overload that would cause apoptotic cell death. Methylation by protein arginine methyl transferase 1 (PRMT1) desensitizes the mitochondrial Ca uptake machinery and reduces mitochondrial Ca accumulation in cancer cells. In case of PRMT1-driven methylation, proper mitochondrial Ca uptake is reestablished by increased activity of uncoupling protein 2 (UCP2), pointing to an importance of these proteins for cancer cell survival and activity. Accordingly, in this study we investigated the impact of UCP2 and PRMT1 on the fate of human lung cancer cells (A549, Calu-3 and H1299) as well as on patients suffering from lung carcinoma. We show that combined overexpression of UCP2 and PRMT1 significantly enhances viability, proliferation as well as mitochondrial respiration. In line with these findings, the overall survival probability of lung carcinoma patients with high mRNA expression levels of UCP2 and PRMT1 is strongly reduced. Furthermore, analysis via The Cancer Genome Atlas (TCGA) reveals upregulation of both proteins, UCP2 and PRMT1, as common feature of various cancer types. These findings suggest that proper mitochondrial Ca uptake is essential for devastating tumor growth, and highlight the importance of a tightly controlled mitochondrial Ca uptake to ensure proper ATP biosynthesis while avoiding dangerous mitochondrial Ca overload. By that, the study unveils proteins of the mitochondrial Ca uptake as potential targets for cancer treatment.
癌细胞已形成独特策略以满足其高能量需求。因此，它们建立了一种由钙触发的高线粒体活性状态。但线粒体钙摄取必须受到严格控制，以避免线粒体钙过载，否则会导致细胞凋亡死亡。蛋白质精氨酸甲基转移酶1（PRMT1）介导的甲基化使线粒体钙摄取机制脱敏，并减少癌细胞中的线粒体钙积累。在PRMT1驱动的甲基化情况下，解偶联蛋白2（UCP2）活性增加可重新建立适当的线粒体钙摄取，这表明这些蛋白质对癌细胞的存活和活性至关重要。因此，在本研究中，我们调查了UCP2和PRMT1对人肺癌细胞（A549、Calu-3和H1299）以及肺癌患者命运的影响。我们发现，UCP2和PRMT1的联合过表达显著提高了细胞活力、增殖以及线粒体呼吸作用。与这些发现一致，UCP2和PRMT1 mRNA表达水平高的肺癌患者的总体生存概率大幅降低。此外，通过癌症基因组图谱（TCGA）分析发现，UCP2和PRMT1这两种蛋白质的上调是各种癌症类型的共同特征。这些发现表明，适当的线粒体钙摄取对于肿瘤的毁灭性生长至关重要，并突出了严格控制线粒体钙摄取以确保适当的ATP生物合成同时避免危险的线粒体钙过载的重要性。由此，该研究揭示了线粒体钙摄取相关蛋白作为癌症治疗的潜在靶点。
