Armando Romina G, Gomez Diego Mengual, Gomez Daniel E
Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Bernal 1876, Buenos Aires, Argentina.
Oncol Rep. 2016 Nov;36(5):2731-2736. doi: 10.3892/or.2016.5094. Epub 2016 Sep 15.
Limitless replicative potential is one of the hallmarks of cancer that is mainly due to the activity of telomerase. This holoenzyme maintains telomere length, adding TTAGGG repetitions at the end of chromosomes in each cell division. In addition to this function, there are extratelomeric roles of telomerase that are involved in cancer promoting events. It has been demonstrated that TERT, the catalytic component of telomerase, acts as a transcriptional modulator in many signaling pathways. Taking into account this evidence and our experience on the study of azidothymidine (AZT) as an inhibitor of telomerase activity, the present study analyzes the effect of AZT on some telomeric and extratelomeric activities. To carry out the present study, we evaluated the transcription of genes that are modulated by the Wnt/β-catenin pathway, such as c-Myc and cyclin-D1 (Cyc-D1) and cell processes related with their expression, such as, proliferation, modifications of the actin cytoskeleton, cell migration and cell cycle in a mammary carcinoma cell line (F3II). Results obtained after treatment with AZT (600 µM) for 15 passages confirmed the inhibitory effect on telomerase. Regarding extratelomeric activities, our results showed a decrease of 64, 38 and 25% in the transcription of c-Myc, Cyc-D1 and TERT, respectively (p<0.05) after AZT treatment. Furthermore, we found an effect on cell migration, reaching an inhibition of 48% (p<0.05) and a significant passage-dependent increase on cell doubling time during treatment. Finally, we evaluated the effect on cell cycle, obtaining a decline in G0/G1 in AZT-treated cells. These results allow us to postulate that AZT is not only an inhibitor of telomerase activity, but also a potential modulator of extratelomeric processes involved in cancer promotion.
无限增殖潜能是癌症的标志之一，这主要归因于端粒酶的活性。这种全酶维持端粒长度，在每个细胞分裂周期的染色体末端添加TTAGGG重复序列。除了这一功能外，端粒酶还具有端粒外功能，参与癌症促进事件。已证明端粒酶的催化成分TERT在许多信号通路中作为转录调节因子发挥作用。考虑到这一证据以及我们在研究叠氮胸苷（AZT）作为端粒酶活性抑制剂方面的经验，本研究分析了AZT对一些端粒和端粒外活性的影响。为了开展本研究，我们评估了受Wnt/β-连环蛋白通路调控的基因的转录情况，如c-Myc和细胞周期蛋白D1（Cyc-D1），以及与其表达相关的细胞过程，如增殖、肌动蛋白细胞骨架修饰、细胞迁移和乳腺癌细胞系（F3II）中的细胞周期。用AZT（600µM）处理15代后获得的结果证实了对端粒酶的抑制作用。关于端粒外活性，我们的结果显示，AZT处理后，c-Myc、Cyc-D1和TERT的转录分别下降了64%、38%和25%（p<0.05）。此外，我们发现对细胞迁移有影响，抑制率达到48%（p<0.05），并且在处理过程中细胞倍增时间有显著的传代依赖性增加。最后，我们评估了对细胞周期的影响，发现AZT处理的细胞在G0/G1期有所下降。这些结果使我们推测，AZT不仅是端粒酶活性的抑制剂，也是癌症促进过程中端粒外过程的潜在调节剂。
