Ait-Aissa Karima, Ebben Johnathan D, Kadlec Andrew O, Beyer Andreas M
Department of Medicine, Medical College of Wisconsin, United States; Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, United States.
Department of Pharmacology & Toxicology, Medical College of Wisconsin,, United States; Cancer Center, Medical College of Wisconsin, United States.
Pharmacol Res. 2016 Sep;111:422-433. doi: 10.1016/j.phrs.2016.07.003. Epub 2016 Jul 6.
Aging, cancer, and chronic disease have remained at the forefront of basic biological research for decades. Within this context, significant attention has been paid to the role of telomerase, the enzyme responsible for lengthening telomeres, the nucleotide sequences located at the end of chromosomes found in the nucleus. Alterations in telomere length and telomerase activity are a common denominator to the underlying pathology of these diseases. While nuclear-specific, telomere-lengthening effects of telomerase impact cellular/organismal aging and cancer development, non-canonical, extra-nuclear, and non-telomere-lengthening contributions of telomerase have only recently been described and their exact physiological implications are ill defined. Although the mechanism remains unclear, recent reports reveal that the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), regulates levels of mitochondrial-derived reactive oxygen species (mtROS), independent of its established role in the nucleus. Telomerase inhibition has been the target of chemotherapy (directed or indirectly) for over a decade now, yet no telomerase inhibitor is FDA approved and few are currently in late-stage clinical trials, possibly due to underappreciation of the distinct extra-nuclear functions of telomerase. Moreover, evaluation of telomerase-specific therapies is largely limited to the context of chemotherapy, despite reports of the beneficial effects of telomerase activation in the cardiovascular system in relation to such processes as endothelial dysfunction and myocardial infarction. Thus, there is a need for better understanding of telomerase-focused cell and organism physiology, as well as development of telomerase-specific therapies in relation to cancer and extension of these therapies to cardiovascular pathologies. This review will detail findings related to telomerase and evaluate its potential to serve as a therapeutic target.
几十年来，衰老、癌症和慢性疾病一直是基础生物学研究的前沿领域。在此背景下，人们对端粒酶的作用给予了极大关注，端粒酶是一种负责延长端粒的酶，端粒是位于细胞核中染色体末端的核苷酸序列。端粒长度和端粒酶活性的改变是这些疾病潜在病理的共同特征。虽然端粒酶的端粒延长作用具有核特异性，会影响细胞/机体衰老和癌症发展，但端粒酶的非经典、核外和非端粒延长作用直到最近才被描述，其确切的生理意义也尚不明确。尽管机制尚不清楚，但最近的报告显示，端粒酶的催化亚基端粒酶逆转录酶（TERT）可调节线粒体衍生的活性氧（mtROS）水平，这与其在细胞核中已确立的作用无关。十多年来，端粒酶抑制一直是化疗（直接或间接）的靶点，但目前尚无FDA批准的端粒酶抑制剂，且很少有处于后期临床试验阶段，这可能是由于对端粒酶独特的核外功能认识不足。此外，尽管有报道称端粒酶激活在心血管系统中对内皮功能障碍和心肌梗死等过程具有有益作用，但端粒酶特异性疗法的评估在很大程度上仅限于化疗背景。因此，有必要更好地了解以端粒酶为重点的细胞和机体生理学，以及开发针对癌症的端粒酶特异性疗法，并将这些疗法扩展到心血管疾病。本综述将详细介绍与端粒酶相关的研究结果，并评估其作为治疗靶点的潜力。
