scholarly journals Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

2016 ◽  
Vol 113 (34) ◽  
pp. E5024-E5033 ◽  
Author(s):  
Priyanka L. Patel ◽  
Anitha Suram ◽  
Neena Mirani ◽  
Oliver Bischof ◽  
Utz Herbig
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Telomerase Activity ◽  
Early Event ◽  
Telomere Dysfunction ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
In Cells

Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc–dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.

scholarly journals Telomerase as a new target for the treatment of hormone-refractory prostate cancer

2004 ◽  
Vol 11 (3) ◽  
pp. 407-421 ◽  
Author(s):  
Annamaria Biroccio ◽  
Carlo Leonetti
Keyword(s):  
Prostate Cancer ◽  
Reverse Transcriptase ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
Reverse Transcriptase Enzyme ◽  
Androgen Ablation

Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia. Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomeraseassociated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.

Telomerase levels control the lifespan of human T lymphocytes

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 849-857 ◽  
Author(s):  
Alexander Röth ◽  
Hans Yssel ◽  
Jérôme Pène ◽  
Elizabeth A. Chavez ◽  
Mike Schertzer ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Major Influence ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Human T Lymphocytes ◽  
Human T Cells

Abstract The loss of telomeric DNA with each cell division contributes to the limited replicative lifespan of human T lymphocytes. Although telomerase is transiently expressed in T lymphocytes upon activation, it is insufficient to confer immortality. We have previously shown that immortalization of human CD8+ T lymphocytes can be achieved by ectopic expression of the human telomerase reverse transcriptase (hTERT) gene, which encodes for the catalytic component of the telomerase complex. To study the role of endogenous hTERT in the lifespan of human T cells, we blocked endogenous hTERT expression by ectopic expression of dominant-negative (DN) hTERT. Cells expressing DN-hTERT had a decreased lifespan and showed cytogenetic abnormalities, including chromosome ends without detectable telomeric DNA as well as chromosome fusions. These results indicate that while endogenous hTERT cannot prevent overall telomere shortening, it has a major influence on the longevity of human T cells. Furthermore, we show that up-regulation of hTERT in T cells upon activation decreases over time in culture. Long-term–cultured T cells also show a decreased expression of c-myc upon activation, resulting in less c-myc–induced transcription of hTERT. Moreover, memory T cells, which have expanded in vivo upon antigen encounter, expressed a lower level of hTERT upon activation than naive cells from the same donor. The observed inverse correlation between telomerase levels and replicative history suggests that telomerase levels in T cells are limiting and increasingly insufficient to sustain their proliferation.

scholarly journals Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 414 ◽  
Author(s):  
Nazmul Huda ◽  
Yan Xu ◽  
Alison M. Bates ◽  
Deborah A. Rankin ◽  
Nagarajan Kannan ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Critical Role ◽  
Telomerase Activity ◽  
Diagnostic Tools ◽  
Early Event ◽  
Molecular Heterogeneity ◽  
Telomere Dysfunction ◽  
Ovarian Carcinogenesis ◽  
Tumor Tissues ◽  
Human Solid Tumors

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.

scholarly journals One-Two Punch Therapy for the Treatment of T-Cell Malignancies Involving p53-Dependent Cellular Senescence

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Yingjie Qing ◽  
Hui Li ◽  
Yunzi Zhao ◽  
Po Hu ◽  
Xiangyuan Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cell ◽  
Cellular Senescence ◽  
Apoptotic Cell ◽  
Telomerase Activity ◽  
Flavonoid Compound ◽  
Antitumor Effects ◽  
Drug Induced ◽  
Human Telomerase Reverse Transcriptase ◽  
T Cell Malignancies

T-cell malignancies are still difficult to treat due to a paucity of plans that target critical dependencies. Drug-induced cellular senescence provides a permanent cell cycle arrest during tumorigenesis and cancer development, particularly when combined with senolytics to promote apoptosis of senescent cells, which is an innovation for cancer therapy. Here, our research found that wogonin, a well-known natural flavonoid compound, not only had a potential to inhibit cell growth and proliferation but also induced cellular senescence in T-cell malignancies with nonlethal concentration. Transcription activity of senescence-suppression human telomerase reverse transcriptase (hTERT) and oncogenic C-MYC was suppressed in wogonin-induced senescent cells, resulting in the inhibition of telomerase activity. We also substantiated the occurrence of DNA damage during the wogonin-induced aging process. Results showed that wogonin increased the activity of senescence-associated β-galactosidase (SA-β-Gal) and activated the DNA damage response pathway mediated by p53. In addition, we found the upregulated expression of BCL-2 in senescent T-cell malignancies because of the antiapoptotic properties of senescent cells. Following up this result, we identified a BCL-2 inhibitor Navitoclax (ABT-263), which was highly effective in decreasing cell viability and inducing apoptotic cell death in wogonin-induced senescent cells. Thus, the “one-two punch” approach increased the sensibility of T-cell malignancies with low expression of BCL-2 to Navitoclax. In conclusion, our research revealed that wogonin possesses potential antitumor effects based on senescence induction, offering a better insight into the development of novel therapeutic methods for T-cell malignancies.

scholarly journals Telomerase activity in primary cultures of normal adrenocortical cells

2001 ◽  
Vol 170 (3) ◽  
pp. 677-684 ◽  
Author(s):  
T Suwa ◽  
L Yang ◽  
PJ Hornsby
Keyword(s):  
Primary Culture ◽  
Adrenal Cortex ◽  
Cell Cultures ◽  
Primary Cultures ◽  
Telomerase Activity ◽  
Adrenocortical Cell ◽  
Isolated Cells ◽  
Adrenocortical Cells ◽  
Human Telomerase Reverse Transcriptase ◽  
In Cells

Telomerase activity was measured in isolated cells from bovine and human adrenal cortex, in cells in primary culture, in cells in later passages in culture, and in cells genetically modified by expression of hTERT (human telomerase reverse transcriptase). Telomerase activity in freshly isolated bovine adrenocortical cells and in human adrenal cells from donors of various ages (6-79 years) was very low or undetected. However, primary bovine adrenocortical cell cultures were strongly positive for telomerase activity, and primary human adrenocortical cell cultures were weakly positive. Both cell types proliferate in primary culture but proliferation of bovine cells is much more vigorous. When primary bovine cells were subcultured to make successively secondary and tertiary cultures, telomerase activity declined strongly, and was undetected by the third passage. There was only a slight decrease in growth rate over this period. Levels of the telomerase RNA component did not change with passage number when assessed by semi-quantitative competitive RT-PCR. When both bovine and human cells were infected with a retrovirus encoding hTERT, telomerase activity in the cells was very high. We conclude that in the adrenal cortex, as in some other tissues, TERT expression is regulated and upregulation of telomerase activity is associated with rapid proliferation in primary culture. Telomerase activity is not maintained, and introduction of TERT is required for stable telomerase activity and for immortalization.

The topoisomerase II catalytic inhibitor ICRF-193 preferentially targets telomeres that are capped by TRF2

2015 ◽  
Vol 308 (5) ◽  
pp. C372-C377 ◽  
Author(s):  
Lianxiang Chen ◽  
Xiaowei Zhu ◽  
Yaru Zou ◽  
Jun Xing ◽  
Eric Gilson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Topoisomerase Ii ◽  
Chromosome Instability ◽  
Telomere Dysfunction ◽  
Telomeric Dna ◽  
Published Evidence ◽  
Catalytic Inhibitor ◽  
Binding Factor ◽  
Therapeutic Molecules

The increased level of chromosome instability in cancer cells is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies kill cells by inducing a nontolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplastic drugs. In the present study, HT1080 cell lines compromised for either telomere repeats binding factor 2 (TRF2) or POT1 were treated with ICRF-193 (3 μM, 24 h) or bleomycin (1 μM, 24 h). DNA damage was assayed by combining telomeric DNA staining of a (CCCTAA)n PNA probe with immunofluorescence of 53BP1 to score the rate of telomere colocalization with 53BP1 foci. We found that ICRF-193, but not bleomycin, leads to DNA damage preferentially at telomeres, which can be rescued by TRF2 inhibition. POT1 inhibition exacerbates telomere dysfunction induced by ICRF-193. Thus, ICRF-193 induces damage at telomeres properly capped by TRF2 but not by POT1. These findings are expected to broaden our view on the mechanism by which conventional therapeutic molecules act to eliminate cancer cells and how to use TRF2 and POT1 levels as surrogate markers for anti-topoisomerase II sensitivity.

Down-regulation of telomerase activity is an early event of cellular differentiation without apparent telomeric DNA change

1998 ◽  
Vol 22 (8) ◽  
pp. 711-717 ◽  
Author(s):  
Osamu Yamada ◽  
Minoko Takanashi ◽  
Makoto Ujihara ◽  
Hideaki Mizoguchi
Keyword(s):  
Cellular Differentiation ◽  
Telomerase Activity ◽  
Early Event ◽  
Telomeric Dna ◽  
Down Regulation

scholarly journals The Expression of Human Telomerase Reverse Transcriptase in Adult Acute Myeloid Leukemia and Its Correlation With Various Clinico-Pathological Parameters

2019 ◽  
Vol 11 (4) ◽  
pp. 25
Author(s):  
Farah AlJobori ◽  
Abdulkareem Mohammad Jaafar
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Telomerase Activity ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
Human Telomerase ◽  
Hematological Remission ◽  
Acute Myeloid

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors (blasts) in the bone marrow and peripheral blood, AML accounts for 80% of acute leukemia in adults, its incidence increase with age. AML can be a fatal disease so research to predict prognosis is important. Telomerase (TA) is an enzyme that stabilizes the telomere length and makes the cell immortal. It is present in some of the normal cells, fetal cells, adult germ cells, and presents in 85% of tumors in humans, it has been shown that TA can be used as a prognostic marker in some solid and hematological neoplasms. Telomere length is a factor that predicts telomere function. AIM: We test the quantitative amount of human telomerase reverse transcriptase (hTERT) gene expression in AML (diagnosed according to FAB) adult and its correlation with various clinic-pathological parameters. PATIENTS & METHODS: We used the TRAP assay to assess the hTERT gene expression in mononuclear blood cells from 40 newly diagnosed AML patients, 25 AML patients after completing their course of treatment, and 15 control health subjects. RESULTS: The mean value of hTERT in AML and control groups were [1.59 ± 1.27 anm and 0.035 ± 0.046 anm respectively], and this difference was significantly higher in patients than in control group (p = 0.0001). The telomerase activity was positive in 27 (67.5%) AML patients, while 13 (32.5%) AML patients were negative for telomerase activity. Twenty-five patients after induction chemotherapy were followed up by bone marrow and peripheral blood examination to determine the patient’s response to therapy. Complete hematological remission was achieved in 12 (48.0%) patients and incomplete hematological remission in 13 (52.0%) patients (14%). The hTERT level was significantly higher in patients before induction chemotherapy than after completion of the induction course (p = 0.0001). The hTERT level at diagnosis in patients who did not achieve complete hematological remission was significantly higher than that in patients who achieved complete hematological remission (p = = 0.026). The hTERT level after induction therapy was significantly higher in patients who did not achieve complete hematological remission than in patients who achieved complete hematological remission (p = 0.003). CONCLUSION: Our research suggests that the hTERT expression could serve as a prognostic marker for AML patients. 

scholarly journals Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins

2016 ◽  
Vol 36 (14) ◽  
pp. 1908-1919 ◽  
Author(s):  
Kyle A. Jay ◽  
Dana L. Smith ◽  
Elizabeth H. Blackburn
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Adaptor Proteins ◽  
Telomerase Activity ◽  
Yeast Cells ◽  
Cell Aging ◽  
Telomeric Dna ◽  
Damage Response ◽  
Dividing Cells

Telomeres cap the ends of chromosomes, protecting them from degradation and inappropriate DNA repair processes that can lead to genomic instability. A short telomere elicits increased telomerase action on itself that replenishes telomere length, thereby stabilizing the telomere. In the prolonged absence of telomerase activity in dividing cells, telomeres eventually become critically short, inducing a permanent cell cycle arrest (senescence). We recently showed that even early after telomerase inactivation (ETI), yeast cells have accelerated mother cell aging and mildly perturbed cell cycles. Here, we show that the complete disruption of DNA damage response (DDR) adaptor proteins in ETI cells causes severe growth defects. This synthetic-lethality phenotype was as pronounced as that caused by extensive DNA damage in wild-type cells but showed genetic dependencies distinct from such damage and was completely alleviated by SML1 deletion, which increases deoxynucleoside triphosphate (dNTP) pools. Our results indicated that these deleterious effects in ETI cells cannot be accounted for solely by the slow erosion of telomeres due to incomplete replication that leads to senescence. We propose that normally occurring telomeric DNA replication stress is resolved by telomerase activity and the DDR in two parallel pathways and that deletion of Sml1 prevents this stress.

scholarly journals Telomerase Activation by Human Papillomavirus Type 16 E6 Protein: Induction of Human Telomerase Reverse Transcriptase Expression through Myc and GC-Rich Sp1 Binding Sites

2001 ◽  
Vol 75 (12) ◽  
pp. 5559-5566 ◽  
Author(s):  
Stephen T. Oh ◽  
Saturo Kyo ◽  
Laimonis A. Laimins
Keyword(s):  
Reverse Transcriptase ◽  
Binding Sites ◽  
Telomerase Activity ◽  
Telomerase Reverse Transcriptase ◽  
Htert Promoter ◽  
Htert Expression ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Transcription ◽  
Human Telomerase ◽  
In Cells

ABSTRACT High-risk human papillomaviruses (HPVs) immortalize keratinocytes by disrupting the retinoblastoma protein (Rb)/p16 pathway and activating telomerase. The E7 oncoprotein targets Rb, while the E6 oncoprotein induces telomerase activity in human keratinocytes. This study has examined the mechanism by which E6 activates telomerase. Expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, was found to be increased in keratinocytes stably expressing HPV type 16 E6, suggesting that E6 acts to increase hTERT transcription. hTERT expression and telomerase activity were activated to significantly higher levels in cells expressing both E6 and E7 than in cells expressing E6 alone. This indicates that E7 may augment E6-mediated activation of hTERT transcription. In transient-transfection assays using hTERT reporters, the induction of hTERT expression by E6 was found to be mediated by a 258-bp fragment of the hTERT promoter, proximal to the ATG initiation codon. Previous studies have demonstrated that overexpression of Myc can activate hTERT expression, suggesting that Myc may be a mediator of E6-mediated hTERT induction. However, in cells stably expressing E6, no strict correlation between the level of Myc and the activation of hTERT was found. Consistent with this observation, mutation of the two Myc binding sites in the hTERT promoter only modestly reduced responsiveness to E6 in transient reporter assays. This indicates that activation of Myc-dependent transcription is not essential for E6-mediated upregulation of hTERT expression. The hTERT promoter also contains five GC-rich elements that can bind Sp1. Mutation of these sites within the 258-bp fragment partially reduced hTERT induction by E6. However, when mutations in the Sp1 sites were combined with the mutated Myc binding sites, all activation by E6 was lost. This indicates that it is the combinatorial binding of factors to Myc and Sp1 cis elements that is responsible for hTERT induction by E6.

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