Clipboard, Search History, and several other advanced features are temporarily unavailable. Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. Inhibition of telomerase activity leads to a very simple expectation: Failure to counteract telomere shortening, the result of incomplete DNA replication, would cause the telomeres to get shorter and shorter and eventually they would become too short to sustain capping, and some signaling process would direct the cells to cease multiplying or even undergo apoptosis. which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. 2002 Mar;2(1):1-17. doi: 10.2174/1568009023334015. government site. Epub 2022 Jul 15. This had the consequence of leaving the telomeric tip uncapped (Fig. Yu GL, Bradley JD, Attardi LD, Blackburn EH. 8600 Rockville Pike Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH In the current work, we investigated the relationship between genetically predicted LTL and lung . Specific association of human telomerase activity with immortal cells and cancer. Please enable it to take advantage of the complete set of features! The "Telomere Erosion in Disposable Soma" theory proposes that replicative loss of telomeric DNA provided a selective advantage during evolution that allowed lifespan to increase by supressing cancer before reproduction (). 2022 Nov 28;13(11):1005. doi: 10.1038/s41419-022-05443-y. "Inhibition of Telomerase activity in human cancer cells by RNA interference". As a result, cancer cells essentially become immortal. This site needs JavaScript to work properly. Kapranov 2007 FANTOMcDNAcDNACarninci 2005 HHS Vulnerability Disclosure, Help Telomerase and the benefits of healthy living. In humans, gradual shortening of telomeres is observed throughout life in many cell types in every part of the body although the cells have a low level of telomerase. The discovery of prevalent mutations in the TERT promoter region in many cancers and recent advances in telomerase biology has led to a renewed interest in targeting this enzyme. official website and that any information you provide is encrypted The component of the telomerase ribonucleoprotein we targeted for knockdown by RNA interference (short interfering RNA or siRNA) was the telomerase RNA. Unable to load your collection due to an error, Unable to load your delegates due to an error. The .gov means its official. An official website of the United States government. As Bernard Weinstein (9) has proposed for other signaling pathways in tumors, cancer cells might be addicted to high levels of telomerase, such that their physiology becomes habituated to it that when telomerase is withdrawn, a cold turkey response is deleterious to the cell. Background: A popular metaphor for what is involved in capping is that the telomere acts in a way comparable to an aglet, which is the end of a shoelace. 2000;10:147154. 1999;97:527538. While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. A universal telomerase RNA core structure includes structured motifs required for binding the telomerase reverse transcriptase protein. 3. The effects were different from the gene expression effects elicited by mutant-template telomerase RNA expression (7). Mol Oncol. While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. Telomerase inhibitor BIBR1532 increases sensitivities of Kras G12D and Kras G12V -Calu-3 cells, Figure 5. An official website of the United States government. R01 CA215733/CA/NCI NIH HHS/United States, P30 CA010815/CA/NCI NIH HHS/United States, P01 CA114046/CA/NCI NIH HHS/United States, R01 CA226888/CA/NCI NIH HHS/United States, R01CA215733/U.S. The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. 2013 Aug 22;32(34):4034-42. doi: 10.1038/onc.2012.402. N Engl J Med. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. Thus, the RNA and the protein of telomerase collaborate in the enzymatic action. Increase Telomerase and Telomeres Naturally. Thus, we converted an effectively immortal, perpetually growing organism into a mortal one by the simple action of making its telomerase nonfunctional, thereby showing that telomerase was important for the continued maintenance of the telomeres and of cell proliferation (3). Cancer Ther 2 (2003): 209 -216. Incorporation of nucleoside analogues into newly synthesized telomeres impairs POT1 binding, causing telomere dysfunction that elicits a DNA damage response and cell death. The ribozyme treatment decreased the metastatic burden. The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures. Epub 2009 Sep 22. Effects of low-level expression of mutant-template telomerase RNA in MCF-7 breast cancer cells. And, indeed, many labs and many groups have now shown that the apparent increase in telomerase is a common feature of human tumor cells. Lai K. L and T.Y.W. Researchers found that the enzyme telomerase, which is active in most tumor cells, may also protect healthy adult cells from becoming cancerous. . 2021 Jan 19;2(1):100186. doi: 10.1016/j.xcrm.2020.100186. Interestingly, despite being continually serially passaged for months, we never observed any reversion or any fast-growing resistant subpopulations growing out from 80 to 100 different clonal lines that were followed. PMC Dybiec J, Szlagor M, Mynarska E, Rysz J, Franczyk B. Int J Mol Sci. Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. Disclaimer, National Library of Medicine 2009;361:23532365. MeSH Tieing together loose ends: telomere instability in cancer and aging. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells. Within a few days, the cell growth rate was markedly decreased. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. The protein component of telomerase, telomerase reverse transcriptase (TERT), is indeed a protein enzyme and its amino acid sequence includes reverse transcriptase motifs. Granger et al. In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. Bookshelf Thus, Ashwagandha root extract has the anti-aging inducing potential. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. One of the telomerase-specific oncolytic adenovirus . This study was published in the prestigious . In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. Ding X, Cheng J, Pang Q, Wei X, Zhang X, Wang P, Yuan Z, Qian D. Int J Radiat Oncol Biol Phys. FOIA In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. Anticancer therapy targeting telomeres and telomerase : current status. Unable to load your collection due to an error, Unable to load your delegates due to an error. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. Findings: The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development. It is this addition of telomeric DNA in increments to the ends of chromosomes that offsets and counterbalances the shortening of chromosome ends. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. Thomas Slaga . Epub 2022 Sep 14. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). We were originally able to show that if we interfered with the action of telomerase in this organism, the telomeres gradually became shorter and cells eventually ceased to divide. Cold Spring Harbor Lab; 2005;19:210010. Enzymatic activity is a fundamental metric of telomerase. DNA methylation of the TERT promoter and its impact on human cancer. Too much telomerase can help confer immortality onto cancer cells and actually increase the likelihood of cancer, . Telomerase activity is essential for the maintenance of critical telomere length, enabling cell replicative immortality, one of the hallmarks of cancer . Our data strengthens the relationship of the Wnt/-catenin pathway and telomere length in the pathogenesis of aCPs. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. Although the mouse telomerase RNA component levels were increased 2-fold and correlated well with proliferation markers, activity levels were increased 10-fold, suggesting a second level of regulation in addition to growth regulation . Does hydatid disease have protective effects against lung cancer? Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. Epub 2011 Jul 23. Before government site. -. DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. Therapies that increase telomerase activity can also slow the rate of telomere shortening. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. The mutated sequence could not bind the DNA sequencespecific protective proteins. The authors declare that they have no conflict of interest. Through this work, we learned, somewhat to our surprise, that we might also be able to incur a more rapid effect on cancer cell growth than expected and even change their cancerous properties in ways that were hitherto unsuspected (7). -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. -, Blasco MA. Reproduced from The Journal of Cell Biology, 2004;167:819830 by copyright permission of The Rockefeller University Press (10). The activity of telomerase is relatively low in somatic cells and absent in normal cells, . Cancers (Basel). Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres.A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes.Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; Furthermore, the underlying DNA is also dynamic, for two reasons. Suspi- M.P. Telomerase as a therapeutic target in glioblastoma. Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. This site needs JavaScript to work properly. Federal government websites often end in .gov or .mil. Epub 2008 Apr 29. We have evaluated the association between telomerase activity and the risk of lung cancer in peripheral blood. Telomerase is commonly expressed in human cancer cells. -, Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. 13. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. Tumor cells in control . Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. In the context of cancer cells, particularly those that are well on the way to a malignant state, telomerase has cancer-promoting properties. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. Clipboard, Search History, and several other advanced features are temporarily unavailable. The fact that telomerase activity declines in somatic cells during adulthood, and that cell transformation and im-mortalization are often associated with increased telom-erase activity (Greider, 1998; Liu, 1999), suggests that telomerase has an antiaging function. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. The telomerase RNA of mouse melanoma cells (B16 cells) was targeted using ribozymes, and the human telomerase RNA in human melanoma cells was targeted using the siRNA approach described previously (8). Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. Indeed, that expected result is exactly what is seen when the telomerase activity in cells is inhibited by, for example, expressing an excess of a catalytically dead version of the protein TERT, which, although it can still assemble into the telomerase ribonucleoprotein complex, forms a complex that is not catalytically active. Interestingly, Zhang et al. Lower left, schematic of the uncapping of telomeres. Increased telomerase activity in mouse skin premalignant progression. Supporting this model, Shang Li, in collaboration with Chris Haqq and his group at University of California, San Francisco, showed that global gene expression profile changed within 4 days after the telomerase RNA was knocked down. The proteins come on and off the telomere with surprising speed. The accumulation of oxidative DNA base damage can severely disrupt the integrity of the genome and is strongly associated with the development of cancer. Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial pap-illary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer. Apoptosis was quantified in clonal lines stably expressing low levels of a mutant-template telomerase RNA construct, a control wild-type RNA construct, or parental MCF-7 cells. Note that not all telomeres (TRF2 spots) overlap with DNA damage foci, although each of the large DNA damage focal spots overlaps with one or more telomeres. J. Mol. Li S, Rosenberg JE, Donjacour AA, et al. 5. Mol Cancer Res (2005) 3 (9): 477-482. Hence, the DNA at the ends of the chromosomes was effectively naked. High telomerase . Clipboard, Search History, and several other advanced features are temporarily unavailable. One reason is that, as was predicted in the 1970s, the known mechanism of DNA polymerase prevents complete DNA replication all the way to the ends of the chromosome at every round of replication. Curr Opin Hematol. FOIA Accessibility Epub 2020 Feb 27. Federal government websites often end in .gov or .mil. With its different RNA template sequence, it makes the sequence at the ends of our chromosomes, T2AG3 repeats, which is very much like that of some ciliated protozoans, T2G4 repeats. Karadayi S, Arslan S, Sumer Z, Turan M, Sumer H, Karadayi K. Mol Biol Rep. 2013 Aug;40(8):4701-4. doi: 10.1007/s11033-013-2565-8. MAIA is designing and evaluating multiple telomere-targeting compounds designed to modify the telomeric structure through the cancer cell - intrinsic telomerase activity - and thus cause the death . Delayed cancer detection is one of the common causes of poor prognosis in case of many cancers including the cancers of the oral cavity. Telomerase is an enzyme that can rebuild telomeres. Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. This work comprises one approach by which one might exploit the increased expression of telomerase, which is so common in cancer cells by forcing them to make toxic telomeres. Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. 2022 Nov 7;10:1060201. doi: 10.3389/fcell.2022.1060201. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. and transmitted securely. Telomerase therapy has been shown to improve healthspan in mice and to increase survival in patients with cancer. 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. Without new synthesis of telomeres at chromosome ends the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. 2012 Feb 1;730(1-2):90-7. doi: 10.1016/j.mrfmmm.2011.07.006. PMC The unexpectedly rapid response to telomerase knockdown prompted us to carry out many controls to rule out possibilities such as targets other than the telomerase RNA being responsible for the effects on cell growth. Telomere end-replication problem and cell aging. Telomerase therapy is a promising approach to treating age-related diseases. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Shang Li and Lifeng Xu showed that when we expressed the mutant-template telomerase RNA, even as early as 3 or 4 days after infection, DNA damage foci appeared at the telomeres, as visualized by immunostaining of the telomere-specific protein TRF2. A. Mutirangura, P. Supiyaphun, +4 . Summary and conclusionsprospects for cancer therapy. This study is registered on the ClinicalTrials.gov website, number NCT00739791. Hence, such a p53-independent apoptotic response is desirable if one is interested in intervening in telomerase action as an anticancer approach. In collaboration with Mohammed Kashani-Sabet and his group at University of California, San Francisco, we examined the effect of telomerase RNA knockdown on metastasis in two in vivo models. False. Larger randomised controlled trials are warranted to confirm the findings of this study. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. In collaboration with Jerry Cunha's lab at University of California, San Francisco, human bladder tumor cells were xenografted under the renal capsule in a mouse. Accessibility Choi JE, Kang HG, Jang JS, Choi YY, Kim MJ, Kim JS, Jeon HS, Lee WK, Cha SI, Kim CH, Kam S, Jung TH, Park JY. . scientists may be able to stop cancer progression and potentially increase mortality. Lancet Oncol. Telomere shortening is counteracted by the cellular enzyme telomerase. PMC Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. Given this nding and the pilot nature of this study, we report . Remember, this enzyme isn't found in . -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. -, Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. Clin Cancer Res. -. Satisfied that the effects indeed resulted specifically from knockdown of the intended telomerase RNA, we analyzed the effects in multiple cell lines. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and An official website of the United States government. doi: 10.1016/j.chembiol.2022.09.002. The https:// ensures that you are connecting to the 2010 Jun 13;151(24):965-70. doi: 10.1556/OH.2010.28899. NOTE: Comparison of human cancer cell growth inhibitory effects predicted and observed when telomerase enzymatic activity was only inhibited (Old) versus those observed in cells in which total telomerase RNA levels were knocked down (New). Thus, telomerase represents an attractive target for highly selective cancer therapeutics. 2013 Oct;14(11):1112-1120. doi: 10.1016/S1470-2045(13)70366-8. . Semeraro MD, Almer G, Renner W, Gruber HJ, Herrmann M. Cells. We used this organism because it has a large number of telomeres and is a relatively rich source of telomerase. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . This response does not require the telomeres to shorten. Primarily, capping is accomplished through formation of a specific DNA-protein complex at the chromosomal terminus. Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction? This site needs JavaScript to work properly. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Our data suggest that Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Aggregation-induced emission luminogens reveal cell cycle-dependent telomerase activity in cancer cells. PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). 2009 Oct;18(10):2773-81. doi: 10.1158/1055-9965.EPI-09-0323. 4. -cancer cells show increased telomerase activity and the telomeres are not shortened. 2003 Nov-Dec;2(6):679-84. Telomere terminal transferase (telomerase) enzyme activity (not the identification of the genes encoding the components of telomerase) was discovered in 1985 in the single-cell organism Tetrahymena ().Almost a decade later, telomerase was described as an almost universal marker in advanced human cancers (), but it was not until 1997 that the catalytic protein component was isolated, first in . Armando R, Cabrera M, Vilarullo R, Chinestrad P, Maggio J, Paderta C, Lorenzano Menna P, Gomez D, Mengual Gmez D. Oncol Rep. 2022 Nov;48(5):188. doi: 10.3892/or.2022.8403. Telomeres are located at the ends of chromosomes and protect them from degradation. Telomerase Activity in Cancer - Telomerase usually active in normal stem cells but expressed in low or null levels in adult cells - Telomerase highly active in 85-95% of cancers (e., colonic adenocarcinoma) - Reactivation of telomerase allows tumour cells to escape apoptosis, causes genomic instability and accumulate further permanent mutations . Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology. Methods: 4). The template is only a minor part of the entire telomerase RNA molecule. 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. That telomerase knockdown produced down-regulation of a specific subset of genes that included those implicated in tumor progression properties, such as metastasis, was intriguing. eCollection 2021. Telomerase activity is decreased in peripheral blood mononuclear cells of hemodialysis patients. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Careers. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Telomerase was found to be highly expressed in dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer in rats, and its high activity was associated with increased TERT expression. Cell Chem Biol. Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. 2022 Oct 30;10(11):2755. doi: 10.3390/biomedicines10112755. 2015 Apr 30;232(1):58-64. doi: 10.1016/j.pscychresns.2015.01.007. 2006 Apr;31(3):277-87. doi: 10.1016/j.psyneuen.2005.08.011. 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