Limits...
Treating Cancer by Targeting Telomeres and Telomerase

View Article: PubMed Central - PubMed

ABSTRACT

Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effects in cancer cells and their role in inhibition of telomerase. We also discuss the current understanding of telomerase in cancer and various therapeutic targets related to the telomeres and telomerase.

No MeSH data available.


Related in: MedlinePlus

(a) The exposed telomere mimicry model hypothesizes that exogenous T11 mimics the exposed endogenous telomere overhang; (b) The cell responds to this mimicry of the telomere overhang exposure by initiating DDRs in cancer cells and triggering upregulation of shelterin proteins in attempt to overcome apparent telomere exposure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384178&req=5

antioxidants-06-00015-f003: (a) The exposed telomere mimicry model hypothesizes that exogenous T11 mimics the exposed endogenous telomere overhang; (b) The cell responds to this mimicry of the telomere overhang exposure by initiating DDRs in cancer cells and triggering upregulation of shelterin proteins in attempt to overcome apparent telomere exposure.

Mentions: From these findings we are able to conclude that there are two potential modes of T-oligo action. We have designated the first mode as the shelterin dissociation model (SDM) and the other we refer to as the exposed telomere mimicry model (ETM). The SDM hypothesizes that the introduction of T11 into the nucleus displaces shelterin proteins from the telomere, thereby critically compromising the telomere secondary structure. It is thought that at least some shelterin proteins bind T11, resulting in the opening of the T-loop causing DDR signaling (Figure 2). The ETM model hypothesizes that T11 accumulates in the nucleus and is recognized as an exposed or damaged telomere, thus initiating DDRs identical to those that occur under normal physiological conditions when telomeres are critically shortened (Figure 3). It is also possible that both potential modes are occurring simultaneously and that T11’s effectiveness is due to both its ability to disrupt the shelterin complex and mimic telomere exposure. In summary, in the exposed telomere mimicry model exogenous T11 mimics the exposed telomere overhang, resulting in initiating DDRs in cancer cells. In the shelterin dissociation model, the presence of T11 in the nucleus causes the disruption of the telomere and the shelterin complex since T11 competes with telomeric DNA for the binding of shelterin proteins, resulting in telomere overhang exposure and initiation of DDRs. Since the activity of telomerase is independent of T11, it will not be modulated in either model [72,73]. Further studies are needed to improve our understanding of these mechanisms.


Treating Cancer by Targeting Telomeres and Telomerase
(a) The exposed telomere mimicry model hypothesizes that exogenous T11 mimics the exposed endogenous telomere overhang; (b) The cell responds to this mimicry of the telomere overhang exposure by initiating DDRs in cancer cells and triggering upregulation of shelterin proteins in attempt to overcome apparent telomere exposure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384178&req=5

antioxidants-06-00015-f003: (a) The exposed telomere mimicry model hypothesizes that exogenous T11 mimics the exposed endogenous telomere overhang; (b) The cell responds to this mimicry of the telomere overhang exposure by initiating DDRs in cancer cells and triggering upregulation of shelterin proteins in attempt to overcome apparent telomere exposure.
Mentions: From these findings we are able to conclude that there are two potential modes of T-oligo action. We have designated the first mode as the shelterin dissociation model (SDM) and the other we refer to as the exposed telomere mimicry model (ETM). The SDM hypothesizes that the introduction of T11 into the nucleus displaces shelterin proteins from the telomere, thereby critically compromising the telomere secondary structure. It is thought that at least some shelterin proteins bind T11, resulting in the opening of the T-loop causing DDR signaling (Figure 2). The ETM model hypothesizes that T11 accumulates in the nucleus and is recognized as an exposed or damaged telomere, thus initiating DDRs identical to those that occur under normal physiological conditions when telomeres are critically shortened (Figure 3). It is also possible that both potential modes are occurring simultaneously and that T11’s effectiveness is due to both its ability to disrupt the shelterin complex and mimic telomere exposure. In summary, in the exposed telomere mimicry model exogenous T11 mimics the exposed telomere overhang, resulting in initiating DDRs in cancer cells. In the shelterin dissociation model, the presence of T11 in the nucleus causes the disruption of the telomere and the shelterin complex since T11 competes with telomeric DNA for the binding of shelterin proteins, resulting in telomere overhang exposure and initiation of DDRs. Since the activity of telomerase is independent of T11, it will not be modulated in either model [72,73]. Further studies are needed to improve our understanding of these mechanisms.

View Article: PubMed Central - PubMed

ABSTRACT

Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effects in cancer cells and their role in inhibition of telomerase. We also discuss the current understanding of telomerase in cancer and various therapeutic targets related to the telomeres and telomerase.

No MeSH data available.


Related in: MedlinePlus