Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, Kerala, India.
J Cell Biochem. 2018 Jun;119(6):4907-4917. doi: 10.1002/jcb.26718. Epub 2018 Mar 7.
Cancer cells exhibit increased dependency on aerobic glycolysis, a phenomenon referred as the "Warburg effect" and therefore, blocking glycolysis by using non-metabolizable analogues of glucose, like 2-Deoxy glucose (2-DG), has been proposed to be of huge therapeutic importance. One of the major drawbacks of using 2-DG as a chemotherapeutic agent is that it can induce ER stress. ER stress is a hall mark in many solid tumors and the unfolded protein response (UPR) associated with it initiates many survival mechanisms in cancer cells. In the present study, we report a novel survival mechanism associated with ER stress, by which the cancer cells become more adapted to aerobic glycolysis. When ER stress was induced in Hela cells by treating them with 2-DG or Thapsigargin (TG) the expression and activity of LDH was significantly up regulated, conferring the cells a greater glycolytic potential. A simultaneous decrease was observed in the expression of miR-23a, which was predicted in silico to have target site on the 3'UTR of LDH A and B mRNAs. miRNA over expression studies and mRNA degradation assays suggest that miR-23a could target LDH A and LDH B mRNAs. Further on the basis of our results and previous scientific reports, we propose that "c-Myc," which is over expressed during ER stress, repress the expression of miR-23a, which in turn regulates the expression of its target genes viz., LDH A and LDH B, thereby making the cells more competent to survive in tumor microenvironment, which requires efficient use of aerobic glycolysis.
癌细胞表现出对有氧糖酵解的依赖性增加，这种现象被称为“Warburg 效应”，因此，通过使用葡萄糖的不可代谢类似物，如 2-脱氧葡萄糖（2-DG）来阻断糖酵解，已被提出具有巨大的治疗意义。使用 2-DG 作为化疗药物的一个主要缺点是它会诱导内质网应激。内质网应激是许多实体瘤的一个主要特征，与之相关的未折叠蛋白反应（UPR）会在癌细胞中引发许多生存机制。在本研究中，我们报道了与内质网应激相关的一种新的生存机制，通过该机制，癌细胞变得更能适应有氧糖酵解。当用 2-DG 或 Thapsigargin（TG）处理 Hela 细胞诱导内质网应激时，LDH 的表达和活性显著上调，赋予细胞更大的糖酵解潜力。同时观察到 miR-23a 的表达下调，这是通过计算机预测 miR-23a 在 LDH A 和 B mRNAs 的 3'UTR 上有靶位点。miRNA 过表达研究和 mRNA 降解实验表明，miR-23a 可以靶向 LDH A 和 LDH B mRNAs。进一步基于我们的结果和以前的科学报告，我们提出“c-Myc”在内质网应激期间过度表达，抑制 miR-23a 的表达，从而反过来调节其靶基因 LDH A 和 LDH B 的表达，使细胞更有能力在肿瘤微环境中存活，这需要有效地利用有氧糖酵解。
