Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Mol Aspects Med. 2010 Feb;31(1):21-8. doi: 10.1016/j.mam.2009.12.001. Epub 2009 Dec 6.
Telomerase (hTERT) activation in cancer cells is an invariable finding resulting in the maintenance of telomere lengths and enhanced replicative capacity. Therefore a variety of therapeutic approaches are being investigated to target hTERT, such as hTERT-promoter driven expression of apoptosis inducing genes, inhibiting telomeric RNA (hTR), and anti-sense or siRNA mediated gene silencing. Whereas, the conventional oncogenic role of hTERT has been linked to its ability to induce replicative senescence and immortalization, evidence is accumulating to support non-canonical activity of hTERT in cancer cells. To that end, hTERT has been implicated in redox-mediated events and its expression has been shown to impact cellular redox status via the recruitment of the mitochondria, a critical intracellular source of reactive oxygen species (ROS). Further evidence in support of the role of mitochondria in hTERT biology comes from findings demonstrating localization of hTERT to the mitochondria, and the ability of hTERT inhibitors to induce mitochondrial-dependent apoptosis in target cells. Here we review the emerging evidence to support the involvement of the mitochondria and intracellular ROS as critical mediators of the non-canonical functions/activity of hTERT with potential implications for its therapeutic targeting in cancer cells.
端粒酶 (hTERT) 在癌细胞中的激活是一个不变的发现，导致端粒长度的维持和增强的复制能力。因此，正在研究各种针对 hTERT 的治疗方法，例如 hTERT 启动子驱动的凋亡诱导基因表达、抑制端粒 RNA (hTR)、反义或 siRNA 介导的基因沉默。然而，hTERT 的传统致癌作用与其诱导复制衰老和永生化的能力有关，越来越多的证据支持 hTERT 在癌细胞中的非典型活性。为此，hTERT 已被牵连到氧化还原介导的事件中，并且其表达已被证明通过招募线粒体来影响细胞氧化还原状态，线粒体是活性氧 (ROS) 的关键细胞内来源。支持线粒体在 hTERT 生物学中的作用的进一步证据来自于发现 hTERT 定位于线粒体，以及 hTERT 抑制剂在靶细胞中诱导线粒体依赖性细胞凋亡的能力。在这里，我们回顾了支持线粒体和细胞内 ROS 作为 hTERT 非典型功能/活性的关键介质的新出现的证据，这可能对其在癌细胞中的治疗靶向具有潜在意义。
