Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.
Biochem Pharmacol. 2018 Oct;156:444-450. doi: 10.1016/j.bcp.2018.09.015. Epub 2018 Sep 15.
Metformin, a commonly used agent in the treatment of type 2 diabetes, is also associated with reduced risk of cancer development and improvement in cancer survival. Although much is known about metformin, the mechanisms behind its anti-cancer properties are not fully understood. In this study we addressed the role of a mitochondrial transporter commonly upregulated in cancer cells, SLC25A10, for cell survival and metabolism in the presence of metformin. SLC25A10 is a carrier in the mitochondrial inner membrane that transports malate and succinate out of the mitochondria, in exchange of phosphate and sulfate. We show that metformin treatment results in decreased gene expression of the SLC25A10 carrier both in lung cancer A549 mock cells and A549 SLC25A10 knockdown (siSLC25A10) cells. The decrease was even more pronounced when cells were grown at low glucose concentrations. The expression levels of key enzymes in glucose metabolism showed slightly altered mean values for all genes tested in both control cells and siSLC25A10 cells upon metformin treatment. The gene expression of the metabolic regulator glutamic-oxaloacetic transaminase 1 decreased in wild type cells upon metformin treatment whereas there was a trend of increased expression in the siSLC25A10 cells upon metformin treatment. In addition, the gene expression of the cyclin-dependent kinase inhibitor 1A was markedly increased in the siSLC25A10 compared to control A549 cells, and with even larger increases in the presence of metformin and at low glucose concentration. Our data show that in siSLC25A10 cell lines, metformin significantly alters the SLC25A10 carrier at both mRNA and protein levels and can thereby affect the supply of nutrients and the metabolic state of cancer cells.
二甲双胍是治疗 2 型糖尿病的常用药物，也与降低癌症发病风险和改善癌症生存有关。虽然人们对二甲双胍了解很多，但它的抗癌特性的机制尚不完全清楚。在这项研究中，我们研究了一种常见于癌细胞的线粒体转运蛋白 SLC25A10 在二甲双胍存在的情况下对细胞存活和代谢的作用。SLC25A10 是一种线粒体内膜中的载体，可将苹果酸和琥珀酸从线粒体中运出，同时交换磷酸盐和硫酸盐。我们发现，二甲双胍处理可降低肺癌 A549 mock 细胞和 A549 SLC25A10 敲低（siSLC25A10）细胞中 SLC25A10 载体的基因表达。当细胞在低糖浓度下生长时，这种降低更为明显。在对照细胞和 siSLC25A10 细胞中，经二甲双胍处理后，所有测试基因的关键酶在葡萄糖代谢中的表达水平均显示出略微改变的平均值。在野生型细胞中，二甲双胍处理后代谢调节因子谷氨酸-草酰乙酸转氨酶 1 的基因表达降低，而在 siSLC25A10 细胞中，二甲双胍处理后表达呈上升趋势。此外，与对照 A549 细胞相比，siSLC25A10 细胞中细胞周期蛋白依赖性激酶抑制剂 1A 的基因表达明显增加，而在存在二甲双胍和低糖浓度的情况下，增加幅度更大。我们的数据表明，在 siSLC25A10 细胞系中，二甲双胍可显著改变 SLC25A10 载体在 mRNA 和蛋白质水平上的表达，从而影响癌细胞的营养供应和代谢状态。
