Targeting. eCollection 2021 Jan 19. These observations lead us to investigate the most efficient means of inhibiting telomerase in cancer cells. It appears that the progressive increase in telomerase activity is associated with the increased level of genomic instability and the phenotypic progression of these premalignant tumors. "Inhibition of Telomerase activity in human cancer cells by RNA interference". Telomerase and the benefits of healthy living. As a result, cancer cells essentially become immortal. (4) showed in a sufficiency experiment that forced ectopic overexpression of telomerase is sufficient to overcome cellular senescence in culture and maintain the telomeres at a steady length as cells continue to divide. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . We used this organism because it has a large number of telomeres and is a relatively rich source of telomerase. 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 . The findings give new insights into cellular aging and the development of cancer. . Methods: 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. The telomerase RNA is built into the structure of the core ribonucleoprotein complex of telomerase, which contains the protein TERT and the telomerase RNA component. The rapid response of telomerase-positive cancer cells to an abrupt depletion of their telomerase despite the lack of telomere uncapping prompted the hypothesis that these effects were unrelated to telomere maintenance or telomere function. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. Epub 2012 Sep 10. 2022 Nov 7;10:1060201. doi: 10.3389/fcell.2022.1060201. One line of evidence for the lack of p53 protein requirement came from the use of a p53-null human colon cancer cell line kindly provided by Dr. Burt Vogelstein. Note: Although not eating fish is better for your telomeres, eating fish isn't necessarily bad for you. . We therefore investigated what happens when you knock down the high levels of telomerase in human cancer cells. Weinstein IB. Telomerase is commonly expressed in human cancer cells. HHS Vulnerability Disclosure, Help 2015;65:87108. Cancers (Basel). 8600 Rockville Pike When compared with the parent cell line, in which the p53 locus is left intact, the responses between the lines were similar. Similarly, using inhibitors of telomerase activity, which prevent telomeric DNA synthesis but do not affect the level of telomerase ribonucleoprotein, elicits the same expected time course of events (Table 1). Unable to load your collection due to an error, Unable to load your delegates due to an error, Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. 8600 Rockville Pike Figure 1. In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. Unlike viral or retroviral reverse transcriptases, such as that of HIV-1, the cellular enzyme telomerase specializes in making the multiple short tandem repeats that are at the ends of chromosomes. 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. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, R01CA226888/U.S. The problem was that previously, the only stable lines that grew out were those that had expressed extremely low levels of mutant-template telomerase RNA. Science. Authors have no potential conflicts of interest to disclose. These cancer cells already had high levels of telomerase, including high levels of the normal wild-type telomerase RNA. 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 . 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 . Li S, Rosenberg JE, Donjacour AA, et al. Approximately 85% of human cancers achieve indefinite cell proliferation and avoidance of telomeric shortening through increased telomerase activity. Nat Rev Genet. Cancer research, 1995. But there are risks. We mutated the telomerase RNA template so that now a mutated DNA sequence was added to the chromosomes, directed by the mutated template. For these immunostaining experiments, we used proteins that are known to accumulate in DNA damage foci at sites of DNA damage, such as the protein hRif1. 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. As described above, the telomeric DNA sequence is specified by copying the telomerase RNA template. A. Mutirangura, P. Supiyaphun, +4 . Previous studies have shown that injecting the telomerase gene into the immune cells (T cells) in our body can help keep the telomeres from getting shorter and enabling them to maintain their anti-viral functioning longer. 2002 Nov;17(6):539-50. doi: 10.1093/mutage/17.6.539. Increased telomerase activity was associated with a decrease in the level of low-density lipoprotein cholesterol (LDL) and a decrease . Thus far, everything discussed has related to telomerase acting in its familiar mode: making telomeric DNA longer. . 2022 Nov 28;13(11):1005. doi: 10.1038/s41419-022-05443-y. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. Telomerase activity in peripheral blood mononuclear cells was measured by a PCR-designed telomeric repeat amplification protocol in 63 lung cancer patients and 190 healthy controls that were matched for age, gender, and smoking status. 8600 Rockville Pike and transmitted securely. These included some intriguing genes, such as cyclin G2 or CDC27genes that have been implicated in cell cycle progression. Biol 1992;225:95160. The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. Proc Am Thorac Soc. This inactive complex swamps out the endogenous telomerase. Strategy for mutant telomere synthesis in human cancer cells. Telomerase inhibitor BIBR1532 prevents Kras G12D -Calu-3 xenograft tumor growth and increases the, Figure 6. Geron Corporation GERN, a late-stage clinical biopharmaceutical company, today highlighted multiple additions to its senior commercial leadership team, as it prepares for the potential . Bethesda, MD 20894, Web Policies Would you like email updates of new search results? Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. Would you like email updates of new search results? Disclaimer, National Library of Medicine Macek P, Poreba R, Gac P, Bogunia-Kubik K, Dratwa M, Wieckiewicz M, Wojakowska A, Michalek-Zrabkowska M, Mazur G, Martynowicz H. Biomedicines. Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . Clipboard, Search History, and several other advanced features are temporarily unavailable. levels of TERT or telomerase activity (Fu et al., 2000). An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. As you might expect, telomerase is active in human stem cells and in germ line cells. -, Blasco MA. The human telomerase RNA, a non-mRNA, can be efficiently knocked down by expression of a short hairpin RNA from a lentiviral construct. 1999;97:527538. Epub 2009 Sep 22. 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. Telomerase as a therapeutic target in glioblastoma. We did something somewhat different: We knocked down the telomerase RNA levels so that now, not only was there less telomerase enzymatic activity but also the cell was depleted of telomerase ribonucleoprotein itself. Moreover, increased telomerase activity enhanced self-renewal ability, proliferation, and differentiation efficiency in Tert-overexpressing ES cells (Armstrong et al, 2005). In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. However, blocking telomerase activity could affect cells where telomerase activity is . The activity of telomerase is relatively low in somatic cells and absent in normal cells, . Furthermore, the underlying DNA is also dynamic, for two reasons. Lin J, Ly H, Hussain A, et al. GFP lane, Northern blot analysis of RNA from cells expressing GFP alone from the control lentiviral vector [adapted from Li et al. In contrast, telomerase activity is silenced in most adult somatic cells. 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. We could achieve up to about 90% knockdown either by using short hairpin siRNAs expressed in the cells from a lentiviral vector expression cassette or by treating the cancer cells with the short synthetic siRNA oligonucleotides with or without modified backbones (Fig. In the case of humans, the repeat sequence T2AG3 is repeated, in tandem, thousands of times at the end of every chromosome. Bethesda, MD 20894, Web Policies Bethesda, MD 20894, Web Policies Alternatively, oligonucleotides complementary to the TERC template region can act as competitive telomerase inhibitors. Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. Keywords: Search for other works by this author on: Greider CW, Blackburn EH. Bethesda, MD 20894, Web Policies Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. 2022 Sep;22(9):515-532. doi: 10.1038/s41568-022-00490-1. 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. US11007255B2 - Cancer vaccines and methods of treatment using the same - Google Patents . 2021 Jan 19;2(1):100186. doi: 10.1016/j.xcrm.2020.100186. Cancer Epidemiol Biomarkers Prev. The pseudoknot is also critically important for the action of telomerase. 1994;266:20115. 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Telomeres and human disease: aging, cancer and beyond. We were, however, unable to rule out the possibility that telomerase activation over such a short time was a compensatory mechanism induced by adverse conditions (eg, a worsening of prostate cancer). Rapid down-regulation of genes promoting cell cycle progression and metastasis. Systematic review of the impact of a plant-based diet on prostate cancer incidence and outcomes. The .gov means its official. 1998 Apr;102(4):397-402. doi: 10.1007/s004390050711. 2021 Jan 2;8(6):nwaa306. Epub 2022 Sep 14. and transmitted securely. 1999;97:50314. They hypothesized that this region was key to regulating telomerase activity and began to experiment on melanoma cells. Background: Although it is not Specific association of human telomerase activity with immortal cells and cancer. The https:// ensures that you are connecting to the Epub 2022 Jul 15. 2009;361:23532365. The mutated sequence could not bind the DNA sequencespecific protective proteins. Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. The primary endpoint was telomerase enzymatic activity per viable cell, measured at . Not all cellsonly about 90% to 95% of the cellswere infected. PBMC telomerase activity in these men increased 29.84% within just 3 months of making significant . Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. For this reason, some have called telomerase the "immortality enzyme." Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells. To a system in which we could perform more short-term analyses, including high levels of telomerase reverse (... -, Shields JM, Pruitt K, McFall a, Der.... 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