Friend or foe? Telomerase as a pharmacological target in cancer and cardiovascular disease

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• 作者：Karima Ait-Aissa^a ; ^b ; ¹ ; Johnathan D. Ebben^c ; ^d ; ¹ ; Andrew O. Kadlec^a ; ^b ; Andreas M. Beyer^a ; ^b ; ^{abeyer@mcw.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ALS ; amyotrophic lateral sclerosis ; ALT ; alternative telomere lengthening mechanisms ; ARIC ; Atherosclerosis risk in communities ; BP ; blood pressure ; CAD ; coronary artery disease ; CML ; chronic myelogenous leukemia ; CVD ; cardiovascular disease ; EC ; endothelial cells ; ET-1 ; endothelin 1 ; GWAS ; genome wide association studies ; H2O2 ; hydrogen peroxide ; ITGB1 ; integrin beta 1 ; NNRTIs ; non-nucleoside reverse transcriptase inhibitors ; NO ; nitric oxide ; PGC-1α ; peroxisome proliferator-activated receptor
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：111
• 期：Complete
• 页码：422-433
• 全文大小：1620 K

文摘

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.