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Telomeres and Telomerase as Targets
for Cancer Therapy: From Telomere Length to Cancer Stem Cell Plasticity
Introduction
Advances in cancer research over
the past several decades have demonstrated that telomeres and telomerase play
crucial roles in cancer initiation, progression, and cellular survival
(Blackburn, 2001; Shay & Wright, 2019). Telomeres are specialized structures
located at the ends of chromosomes that protect genetic material from
degradation and instability during DNA replication (de Lange, 2005). In normal
somatic cells, telomeres progressively shorten with each cell division until
they reach a critical length, triggering cellular senescence or programmed cell
death (apoptosis) (Harley et al., 1990). In contrast, most cancer cells
maintain their telomere length through the reactivation of telomerase, thereby
acquiring the capacity for unlimited proliferation and cellular immortality
(Kim et al., 1994; Shay & Bacchetti, 1997).
The schematic illustration above
depicts the complex interactions among telomere length, telomerase activity,
G-quadruplex structures, poly(ADP-ribosyl)ation modifications, and cancer stem
cell plasticity, all of which have become major focal points in the development
of modern anticancer therapies.
The Relationship Between Cancer and
Telomere Length
Telomeres consist of repetitive DNA
sequences that serve as protective caps at chromosome ends. During each round
of cell division, a small portion of telomeric DNA is lost due to the
limitations of the DNA replication machinery, a phenomenon known as the
end-replication problem (Olovnikov, 1973; Blackburn, 2001). In normal cells,
continuous telomere shortening results in:
- Cell
cycle arrest (senescence).
- Activation
of DNA damage response pathways.
- Programmed
cell death (apoptosis) (d’Adda di Fagagna et al., 2003).
However, cancer cells frequently
reactivate telomerase, enabling the maintenance of telomere length. Telomerase
replenishes lost telomeric DNA sequences, allowing cancer cells to proliferate
indefinitely (Kim et al., 1994; Shay & Wright, 2019). As illustrated in the
schematic, progressive telomere shortening ultimately leads to cellular
senescence and death, whereas telomerase activation promotes telomere
maintenance and supports the survival and expansion of malignant cells.
The Telomere Complex: Roles of TRF1
and TERRA
The biological function of
telomeres is determined not only by their length but also by a variety of
proteins and RNA molecules that interact with them (de Lange, 2005).
TRF1 (Telomeric Repeat-Binding
Factor 1)
TRF1 is a critical component of the
shelterin complex that regulates telomere stability and length (Palm & de
Lange, 2008). This protein controls telomerase access to chromosome ends and
preserves telomeric structural integrity. Disruption of TRF1 function may lead
to:
- Chromosomal
instability.
- Activation
of DNA damage responses.
- Altered
cancer cell proliferation (MartÃnez et al., 2009).
Consequently, TRF1 has emerged as a
promising target for anticancer therapeutic strategies.
TERRA (Telomeric Repeat-Containing
RNA)
TERRA is a long non-coding RNA
transcribed from telomeric regions (Azzalin et al., 2007). It plays important
roles in:
- Regulation
of telomere length.
- Formation
and maintenance of telomeric chromatin structures.
- Modulation
of telomerase activity (Azzalin & Lingner, 2015).
Recent studies have shown that
alterations in TERRA expression can influence the progression of various
cancers, suggesting its potential utility as both a biomarker and a therapeutic
target (Cusanelli & Chartrand, 2015).
From “Length” to “Structure”:
Targeting G-Quadruplexes
The current paradigm of telomere
research extends beyond telomere length and increasingly focuses on the
three-dimensional structural organization of telomeric DNA. One of the most
extensively studied structures is the G-quadruplex (G4), a secondary DNA structure
formed within guanine-rich (G-rich) regions of the genome (Neidle &
Balasubramanian, 2006).
Figure 1. Three-dimensional
structure of a transfer RNA (tRNA) molecule represented in ribbon and
nucleotide-base models.
Different colors indicate the
orientation and spatial positions of nucleotides along the RNA chain. The
structure exhibits the characteristic folding pattern of tRNA, forming an
L-shaped three-dimensional conformation as a result of intramolecular base-pairing
interactions and hydrogen bonding. One end contains the anticodon, a nucleotide
sequence responsible for recognizing complementary codons on messenger RNA
(mRNA) during translation, whereas the opposite end forms the acceptor stem,
which serves as the attachment site for amino acids. This unique architecture
enables tRNA to function as a molecular adaptor, linking the genetic
information encoded in mRNA to the corresponding amino acid sequence during
protein synthesis.
Figure 2. Mechanism of telomere
maintenance and oncogene expression inhibition by G-quadruplex (G4) ligands in
cancer cells.
Cancer cells maintain telomere
length through two principal mechanisms: telomerase activation and the
Alternative Lengthening of Telomeres (ALT) pathway. G4 ligands promote the
formation and stabilization of G-quadruplex structures within telomeric regions
and gene promoters, thereby inhibiting telomerase activity, inducing telomere
shortening, and suppressing the transcription of several oncogenes, including TERT,
C-MYC, BCL2, KRAS, and VEGF. In cells that rely on the ALT pathway,
G4 ligands can also stabilize G-loop structures, which may serve as promising
therapeutic targets for anticancer interventions. Overall, the formation and
stabilization of G-quadruplex structures contribute to the inhibition of cancer
cell proliferation by disrupting telomere maintenance mechanisms and modulating
oncogene expression.
Figure 3. Structure and topology of
G-quadruplexes (G4) formed by guanine-rich nucleic acid sequences.
The upper panel illustrates the
formation of a G-tetrad, a planar structure composed of four guanine bases
connected through Hoogsteen hydrogen bonds and stabilized by the presence of a
central monovalent or divalent cation (M⁺). Stacking of multiple G-tetrads
gives rise to a stable G-quadruplex (G4) structure. G-quadruplexes may form
through intramolecular folding, in which a single nucleic acid strand
folds upon itself to generate a G4 structure, or through intermolecular
association, where two or more nucleic acid strands assemble to form a G4
complex. The lower panel depicts the major G-quadruplex topologies, including parallel,
antiparallel, and hybrid (mixed) conformations, which are
distinguished by strand orientation (indicated by arrows) and the arrangement
of loop regions connecting guanine-rich segments. These structural variations
influence the stability, biological functions, and molecular recognition
properties of G-quadruplexes.
G-Quadruplex Formation and Its
Therapeutic Implications
The formation of G-quadruplex
structures can:
- Inhibit
telomerase activity.
- Interfere
with DNA replication in cancer cells.
- Activate
DNA damage signaling pathways.
- Suppress
tumor proliferation (Mergny & Sen, 2019).
Because most cancer cells depend on
telomerase activity for unlimited proliferation, stabilization of G-quadruplex
structures using small molecules has emerged as a highly promising therapeutic
strategy (Neidle, 2017). This approach enables a more specific inhibition of
cancer growth compared with conventional chemotherapy.
Poly(ADP-ribosyl)ation and
Tankyrase as Emerging Therapeutic Targets
The above scheme also highlights
the importance of poly(ADP-ribosyl)ation in the regulation of telomeres and
cancer signaling pathways (Lehtiö et al., 2013). A key protein involved in this
process is Tankyrase, an enzyme belonging to the PARP (Poly ADP-ribose
Polymerase) family (Smith et al., 1998).
1.
Telomere Regulation
Tankyrase modifies telomeric
proteins through poly(ADP-ribosyl)ation, thereby influencing telomerase access
to chromosome ends (Cook et al., 2002).
Elevated tankyrase activity can:
- Promote
telomere elongation.
- Support
cancer cell immortality.
- Facilitate
tumor growth (Seimiya et al., 2005).
2.
Regulation of the Wnt/β-Catenin Pathway
Tankyrase also plays a critical
role in regulating Axin, an essential component of the Wnt signaling pathway
(Huang et al., 2009).
When tankyrase is active:
- Axin
undergoes degradation.
- β-catenin
becomes stabilized.
- The
Wnt signaling pathway is activated.
- Cancer
cell proliferation increases (Lau et al., 2013).
Therefore, the development of
tankyrase inhibitors is expected to provide dual therapeutic benefits by
simultaneously inhibiting telomere maintenance and suppressing tumor growth
mediated through the Wnt/β-catenin pathway.
Tumor Plasticity and Heterogeneity
One of the greatest challenges in
cancer therapy is the presence of cancer stem cells (CSCs) (Batlle &
Clevers, 2017).
Cancer stem cells possess the
ability to:
- Self-renew.
- Differentiate
into various tumor cell types.
- Survive
chemotherapy and radiotherapy.
- Initiate
tumor recurrence following treatment (Reya et al., 2001).
The scheme above illustrates the
relationship between telomerase activity and the self-renewal capacity of
cancer stem cells. High telomerase activity helps maintain the regenerative
potential of CSCs, enabling cancer cell populations to persist over time
(Flores et al., 2008).
Drug Resistance and Tumor
Recurrence
Although anticancer therapies can
eliminate the majority of tumor cells, a small population of CSCs often
survives treatment. These surviving cells may subsequently regenerate tumors
that are more resistant to therapy (Batlle & Clevers, 2017).
This phenomenon is associated with:
- Drug
resistance.
- Tumor
recurrence.
- Tumor
heterogeneity (Meacham & Morrison, 2013).
Consequently, the identification of
CSC-specific molecular targets has become a major focus in the development of
next-generation cancer therapies.
Integration of Multiple
Telomere-Based Therapeutic Targets
Three major directions have emerged
in the development of telomere-based cancer therapies:
1. Targeting G-Quadruplex
Structures
- Inhibition
of telomerase activity.
- Disruption
of cancer DNA replication.
- Induction
of tumor cell death.
2. Inhibition of Tankyrase and
Poly(ADP-ribosyl)ation
- Reduction
of telomere elongation.
- Suppression
of Wnt/β-catenin signaling.
- Inhibition
of cancer cell proliferation.
3. Targeting Cancer Stem Cells
- Reduction
of self-renewal capacity.
- Suppression
of drug resistance.
- Prevention
of tumor recurrence.
This multimodal therapeutic
strategy is expected to provide greater efficacy than conventional approaches
that primarily target tumor cell proliferation (Shay & Wright, 2019).
CONCLUSION
Telomeres and telomerase are
fundamental components of cancer biology and have become among the most
promising targets for anticancer therapy (Blackburn, 2001; Shay & Wright,
2019). Modern research has expanded beyond the study of telomere length alone
to encompass G-quadruplex structures, regulation by TERRA and TRF1, tankyrase
activity, and their interactions with cancer stem cells.
A deeper understanding of these
mechanisms provides new opportunities for the development of more specific,
effective, and less toxic anticancer therapies. In the future, combinations of
telomerase inhibitors, G-quadruplex stabilizers, tankyrase inhibitors, and
therapies targeting cancer stem cells may represent a powerful strategy for
overcoming drug resistance and preventing tumor recurrence.
DAFTAR PUSTAKA
Azzalin, C.M., Reichenbach, P.,
Khoriauli, L., Giulotto, E., & Lingner, J. (2007). Telomeric
repeat-containing RNA and RNA surveillance factors at mammalian chromosome
ends. Science, 318(5851), 798–801.
Azzalin, C.M., & Lingner, J.
(2015). Telomeres: the silence is broken. Cell Cycle, 14(7),
998–1000.
Batlle, E., & Clevers, H.
(2017). Cancer stem cells revisited. Nature Medicine, 23(10),
1124–1134.
Blackburn, E.H. (2001). Switching
and signaling at the telomere. Cell, 106(6), 661–673.
Cook, B.D., Dynek, J.N., Chang, W.,
Shostak, G., & Smith, S. (2002). Role for the related poly(ADP-ribose)
polymerases tankyrase 1 and 2 at human telomeres. Molecular and
Cellular Biology, 22(1), 332–342.
Cusanelli, E., & Chartrand, P.
(2015). Telomeric noncoding RNA: Telomeric repeat-containing RNA in telomere
biology. Wiley Interdisciplinary Reviews RNA, 6(4), 407–419.
d’Adda di Fagagna, F., Reaper,
P.M., Clay-Farrace, L., et al. (2003). A DNA damage checkpoint response in
telomere-initiated senescence. Nature, 426, 194–198.
de Lange, T. (2005). Shelterin: the
protein complex that shapes and safeguards human telomeres. Genes &
Development, 19(18), 2100–2110.
Flores, I., Cayuela, M.L., &
Blasco, M.A. (2008). Effects of telomerase and telomere length on epidermal
stem cell behavior. Science, 309(5738), 1253–1256.
Harley, C.B., Futcher, A.B., &
Greider, C.W. (1990). Telomeres shorten during ageing of human
fibroblasts. Nature, 345, 458–460.
Huang, S.M.A., Mishina, Y.M., Liu,
S., et al. (2009). Tankyrase inhibition stabilizes Axin and antagonizes Wnt
signalling. Nature, 461, 614–620.
Kim, N.W., Piatyszek, M.A., Prowse,
K.R., et al. (1994). Specific association of human telomerase activity with
immortal cells and cancer. Science, 266(5193), 2011–2015.
Lau, T., Chan, E., Callow, M., et
al. (2013). A novel tankyrase small-molecule inhibitor suppresses APC
mutation-driven colorectal tumor growth. Cancer Research, 73(10),
3132–3144.
Lehtiö, L., Collins, R., van den
Berg, S., et al. (2013). Tankyrases: structure, function and therapeutic
implications in cancer. Current Pharmaceutical Design, 19(23),
6472–6488.
MartÃnez, P., Thanasoula, M.,
Muñoz, P., et al. (2009). Increased telomere fragility and fusions resulting
from TRF1 deficiency. EMBO Journal, 28(13), 1819–1830.
Meacham, C.E., & Morrison, S.J.
(2013). Tumour heterogeneity and cancer cell plasticity. Nature,
501, 328–337.
Mergny, J.L., & Sen, D. (2019).
DNA quadruple helices in nanotechnology. Chemical Reviews, 119(10),
6290–6325.
Neidle, S. (2017). Quadruplex
nucleic acids as targets for anticancer therapeutics. Nature Reviews
Chemistry, 1, 0041.
Neidle, S., & Balasubramanian,
S. (2006). Quadruplex Nucleic Acids. Cambridge: Royal Society of
Chemistry.
Olovnikov, A.M. (1973). A theory of
marginotomy. Journal of Theoretical Biology, 41(1), 181–190.
Palm, W., & de Lange, T.
(2008). How shelterin protects mammalian telomeres. Annual Review of
Genetics, 42, 301–334.
Reya, T., Morrison, S.J., Clarke,
M.F., & Weissman, I.L. (2001). Stem cells, cancer, and cancer stem
cells. Nature, 414, 105–111.
Seimiya, H., Muramatsu, Y., Ohishi,
T., & Tsuruo, T. (2005). Tankyrase 1 as a target for telomere-directed
molecular cancer therapeutics. Cancer Cell, 7(1), 25–37.
Shay, J.W., & Bacchetti, S.
(1997). A survey of telomerase activity in human cancer. European
Journal of Cancer, 33(5), 787–791.
Shay, J.W., & Wright, W.E.
(2019). Telomeres and telomerase: three decades of progress. Nature
Reviews Genetics, 20(5), 299–309.
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