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.

Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction

“…In translating these findings, it will be important to consider the effects of upregulating telomerase in noncardiac diseases. For example, although not an oncogene, TERT is involved in support of tumor growth and metastasis (1). The risk versus benefit of TERT activation or inhibition needs to be carefully considered in different cell types.…”

“…The risk versus benefit of TERT activation or inhibition needs to be carefully considered in different cell types. Current evidence indicates that the proliferative functions of TERT are driven by its canonical telomere nuclear lengthening effects (1). Separating mitochondrial and nuclear actions of telomerase would help advance further discovery in this field.…”

Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection—The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

“…In addition to the nuclear and nucleolar localization, telomerase also attains cytoplasmic and mitochondrial localizations, which have strong implications with cardiovascular diseases. It is known that hTERT contains a N-terminal mitochondrial targeting sequence, which is crucial for its mitochondrial translocation [ 45 , 46 ]. Beyer et al [ 37 ] have demonstrated that hTERT shuttles directly to the mitochondria under oxidative stress, a characteristic of cardiovascular disease [ 47 ].…”

Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration

“…There are reports about the use of telomerase as a therapeutic tissue-specific target for diseases of the cardiovascular system [61,62]. Telomerase can be used to treat coronary heart disease due to protection against ROS [63,64]. With ischemia reperfusion injury, telomerase deficiency leads to heart failure [65].…”