Review
Telomerase: Key regulator of inflammation and cancer

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Abstract

The telomerase holoenzyme, which has a highly conserved role in maintaining telomere length, has long been regarded as a high-profile target in cancer therapy due to the high dependency of the majority of cancer cells on constitutive and elevated telomerase activity for sustained proliferation and immortality. In this review, we present the salient findings in the telomerase field with special focus on the association of telomerase with inflammation and cancer. The elucidation of extra-telomeric roles of telomerase in inflammation, reactive oxygen species (ROS) generation, and cancer development further complicated the design of anti-telomerase therapy. Of note, the discovery of the unique mechanism that underlies reactivation of the dormant telomerase reverse transcriptase TERT promoter in somatic cells not only enhanced our understanding of the critical role of TERT in carcinogenesis but also opens up new intervention ideas that enable the differential targeting of cancer cells only. Despite significant effort invested in developing telomerase-targeted therapeutics, devising efficacious cancer-specific telomerase/TERT inhibitors remains an uphill task. The latest discoveries of the telomere-independent functionalities of telomerase in inflammation and cancer can help illuminate the path of developing specific anti-telomerase/TERT therapeutics against cancer cells.

Introduction

Telomeres are special regions located at the ends of chromosomes that protect chromosomal ends from DNA damage or fusion [[1], [2], [3], [4], [5]]. The telomerase holoenzyme complex maintains telomere length through the addition of G-rich repetitive sequences such as TTAGGG in vertebrates [[6], [7], [8], [9]]. In most human somatic cells, telomere length will shorten with every cell division [10,11]. When telomeres reach a critical length, replicative senescence or cell death will be triggered [[12], [13], [14]]. The physiological shortening of telomeres is a hallmark of cellular aging. Telomere shortening can be accelerated by several stimuli including oxidative stress and inflammation [[15], [16], [17], [18], [19], [20]]. Although the association between mutations in telomerase-associated genes and inflammation dysregulation is known, the mechanics behind the crosstalk between telomere/telomerase and inflammation is still unclear. In this review, we present the insights gathered over the years on the role of telomerase in inflammation and tumorigenesis.

Section snippets

Overview of telomerase

Telomerase is a ribonucleoprotein complex that consists of several components including TERT, telomerase RNA component (TERC) that serves as a template for adding telomere repeats [[21], [22], [23], [24]], the protein dyskerin, and other associated proteins including the small nucleolar RNA-associated protein (NOP1), nucleolar protein family A member 1 (GAR1), nucleolar protein family A member 2 (NHP2) and NHP3 (NOP1) [[25], [26], [27], [28]] (Fig. 1). The nucleolar protein dyskerin, encoded by

Telomerase and inflammation

Inflammation is the body’s intrinsic biological defense response to different stimuli such as pathogens and it contributes to the clearance and elimination of harmful stimuli. In general, inflammation can be divided into two groups: acute inflammation and chronic inflammation [[66], [67], [68], [69], [70], [71], [72], [73], [74], [75]]. Acute inflammation can be induced by tissue injury or microbial invasion and lasts for a relatively short duration. This response increases blood flow and

Telomerase and oxidative stress

Redox signaling plays a critical role in the regulation of physiological processes. Oxidative stress, which results from the dysregulation or disruption of redox signaling, is a hallmark of many pathologies, such as Alzheimer’s disease, Parkinson's disease and neurodegenerative diseases [[114], [115], [116], [117], [118], [119]]. The hypoxic environment of cancer cells promotes the initiation of redox signaling that can modulate their metabolism, proliferation, as well as immune response [[120]

TERT and cancer

The telomerase enzyme, which is active in proliferative cells, stem cells, germ cells but inactive in most human somatic cells, was found to be reactivated in approximately 90 % of cancer cells [169]. Known mechanisms of TERT reactivation include increased TERT copy number [170], TERT gene amplification [171], genomic rearrangements [172,173], long-range interactions [174] and several point mutations at the promoter region of the TERT gene [175] that can increase TERT mRNA expression and TERT

Telomerase-targeted cancer therapies

Telomerase has been an emerging target in cancer therapy as it is essential for the progression of different cancer types as well as cancer stem cells. The low telomerase activity in normal cells but not in cancer cells forms the basis of anti-telomerase cancer therapy. In this section, we will discuss the current telomerase-targeted cancer approaches (Fig. 6).

Small molecule telomerase inhibitors such as the non-nucleoside reverse transcriptase inhibitor BIBR1532 was found to inhibit telomerase

Discussion

Although it has only been approximately 35 years after the discovery of telomerase function in telomere elongation, our understanding of telomerase function has increased tremendously within this short span of time. As presented in this review, TERT is implicated in non-canonical roles including modulation of inflammation; its dual role in oxidative stress and subsequent downstream effects such as mitochondrial DNA damage and ROS generation; the contribution of exogenous and endogenous factors

Innovation

Emerging non-canonical roles of telomerase, which include fine-tuning inflammation, reactive oxygen species generation, and cancer development, can potentially broaden the range of telomerase-targeted strategies and circumvent the limitations of conventional therapeutic approaches. Examples of novel therapeutic strategies that have been developed include combination therapy comprising of telomerase inhibitors and antioxidants, as well as selective inhibition of TERT transcription in cancer

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2018R1D1A1B07042969). We thank the Agency for Science Technology and Research (A*STAR) and Singapore National Research Foundation (NRF-CRP17-2017-02) for funding and support to the V.T. laboratory.

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      Citation Excerpt :

      In the telomerase activity in humans, there are two subunits in it – one is the human telomerase reverse transcriptase (hTERT), and the other one is the human telomerase RNA (hTR) [219]. The telomerase inhibitor Imetelstat, an oligonucleotide telomerase antisense inhibitor, basically prevents the holoenzyme assembly in telomerase by binding with the RNA component by competing with the catalytic component of telomerase enzyme and binds to the region with high affinity [220]. Imetelstat has been successful past the second clinical trial phase and is effective in treating and preventing further growth of cancer cells in breast cancer, myelomas, etc. [220].

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      Citation Excerpt :

      Telomerase is a ribonucleoprotein complex composed of telomerase reverse transcriptase (TERT) and template RNA component (TERC), which is responsible for maintaining telomere stability and regulating cell growth and proliferation. Generally, normal human cells will reach the Hayflick limit after 50–70 times of division, resulting in cell aging and death [1,2]. However, in more than 85% of cases in cancers, telomerase is overexpressed, and high levels of telomerase will maintain telomere length by adding 5′-TTAGGG-3′ sequence repeats to the ends of the telomere to maintain the proliferation of cancer cells [3,4].

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    1

    Both Lele Wu and Kerem Fidan contributed equally to this study.

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