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

Abstract

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.

Keywords: Aging; Cancer; Cardiovascular disease; Reactive oxygen species; Telomerase.

Figure 1. Differential regulation of telomerase within vascular tissue

Within the Endothelial cells (EC), increased telomerase activity mediates increase of nitric oxide (NO) bioavailability, antioxidant levels and anti-senescent phenotype and therefore prevents the progression of atherosclerosis. Unlike the EC, telomerase activated in smooth muscle cells (SMC) increases proliferation-induced hypoxia and promotes atherosclerosis progression.

Figure 1. Telomerase regulation under cardiovascular diseases vs Cancer

By its mitochondrial targeted (_mtTERT) function, telomerase activity induces beneficial and protective effects during cardiovascular disease. While in cancer, its nuclear targeted (_nucTERT) inhibition is necessary to reverse the immortal, proliferative and chemo-resistance phenotype.