Saretzki G
Institute for Ageing and Health, Campus for Ageing and Vitality Edwardson Building, Newcastle upon Tyne, NE4 5PL, UK.
Curr Pharm Des. 2014;20(41):6386-403. doi: 10.2174/1381612820666140630095606.
Telomerase activity is essential for human cancer cells in order to maintain telomeres and provide unlimited proliferation potential and cellular immortality. However, additional non-telomeric roles emerge for the telomerase protein TERT that can impact tumourigenesis and cancer cell properties. This review summarises our current knowledge of non-telomeric functions of telomerase in human cells, with a special emphasis on cancer cells. Non-canonical functions of telomerase can be performed within the nucleus as well as in other cellular compartments. These telomereindependent activities of TERT influence various essential cellular processes, such as gene expression, signalling pathways, mitochondrial function as well as cell survival and stress resistance. Emerging data show the interaction of telomerase with intracellular signalling pathways such as NF-κB and WNT/β-catenin; thereby contributing to inflammation, epithelial to mesenchymal transition (EMT) and cancer invasiveness. All these different functions might contribute to tumourigenesis, and have serious consequences for cancer therapies due to increased resistance against damaging agents and prevention of cell death. In addition, TERT has been detected in non-nuclear locations such as the cytoplasm and mitochondria. Within mitochondria TERT has been shown to decrease ROS generation, improve respiration, bind to mitochondrial DNA, increase mitochondrial membrane potential and interact with mitochondrial tRNAs. All these different non-telomere-related mechanisms might contribute towards the higher resistance of cancer cells against DNA damaging treatments and promote cellular survival. Understanding these different mechanisms and their complexity in cancer cells might help to design more effective cancer therapies in the future.
端粒酶活性对于人类癌细胞至关重要，以便维持端粒并提供无限增殖潜能和细胞永生化。然而，端粒酶蛋白TERT出现了额外的非端粒作用，这些作用会影响肿瘤发生和癌细胞特性。本综述总结了我们目前对人类细胞中端粒酶非端粒功能的认识，特别强调了癌细胞。端粒酶的非经典功能可在细胞核以及其他细胞区室中发挥。TERT的这些不依赖端粒的活性影响各种重要的细胞过程，如基因表达、信号通路、线粒体功能以及细胞存活和应激抗性。新出现的数据表明端粒酶与细胞内信号通路如NF-κB和WNT/β-连环蛋白相互作用；从而导致炎症、上皮-间质转化（EMT）和癌症侵袭性。所有这些不同功能可能都有助于肿瘤发生，并且由于对损伤因子的抗性增加和细胞死亡的预防，对癌症治疗产生严重后果。此外，已在细胞质和线粒体等非核位置检测到TERT。在线粒体内，TERT已被证明可减少活性氧生成、改善呼吸作用、与线粒体DNA结合、增加线粒体膜电位并与线粒体tRNA相互作用。所有这些不同的与端粒无关的机制可能都有助于癌细胞对DNA损伤治疗具有更高的抗性并促进细胞存活。了解癌细胞中这些不同机制及其复杂性可能有助于未来设计更有效的癌症治疗方法。
