Lancet Oncol. The primary endpoint was telomerase enzymatic activity per viable cell, measured at . Telomerase inhibitor BIBR1532 increases sensitivities of Kras G12D and Kras G12V -Calu-3 cells, Figure 5. This was first shown in a model organism, the ciliate Tetrahymena, and subsequently in many other organisms. . 2013 Oct;14(11):1112-1120. doi: 10.1016/S1470-2045(13)70366-8. Mol Oncol. The site is secure. 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). Elizabeth H. Blackburn; Telomerase and Cancer: Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture. Targeting. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. MeSH Similar findings were also made in the setting of a simple xenograft model: When we xenografted human cancer cells expressing the mutant-template telomerase RNA into a mouse model, we saw greatly decreased tumor growth and some regression of the tumors, accompanied by high rates of apoptosis in the tumors (5). To detect telomerase, a novel surface-enhanced Raman scattering (SERS) biosensor was constructed using the dual DNA-catalyzed amplification strategy composed of strand displacement amplification (SDA . Telomere length and the risk of lung cancer. Enzymatic activity is a fundamental metric of telomerase. At various levels, it is also active in other adult human cells, but the levels are often very low and not enough to sustain telomere length over a lifetime. Kras mutations upregulate TERT expression, Figure 1. These proteins include DNA sequencespecific binding proteins and other proteins that together, in effect, sheathe the chromosome end. 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. PMC The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures. 2003 Oct 1;289(2):326-34. doi: 10.1016/s0014-4827(03)00281-7. Telomerase has been considered as a biomarker for early diagnosis and prognosis assessment of hepatocellular carcinoma (HCC), while the highly sensitive and specific methods remain challenging. Humans also have telomerase. Once again, the effects did not require p53 (7). The .gov means its official. A delay ensues, during which telomeres shorten, before the cells finally cease to grow. In humans, telomerase enzyme activity is absent in most normal cells but present in the majority of tumors (4). Ding X, Cheng J, Pang Q, Wei X, Zhang X, Wang P, Yuan Z, Qian D. Int J Radiat Oncol Biol Phys. Ferrara MG, Stefani A, Pilotto S, Carbone C, Vita E, Di Salvatore M, D'Argento E, Sparagna I, Monaca F, Valente G, Vitale A, Piro G, Belluomini L, Milella M, Tortora G, Bria E. Front Oncol. 2005;19:21002110. 2021 Dec 16;13(24):6332. doi: 10.3390/cancers13246332. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). Finally, we observed the same kinds of rapid growth inhibitory effects in the context of a more in vivolike setting for tumor cells. Immunity. Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. 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. Epub 2009 Sep 22. Reproduced from The Journal of Cell Biology, 2004;167:819830 by copyright permission of The Rockefeller University Press (10). Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. -, Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. Accessibility Telomerase, the enzyme that reduces telomere shortening in certain cells, is reactivated or increased in more than 90 percent of cancers, found a 2016 study. False. Immunotherapies, MeSH 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. Cell Chem Biol. Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. Larger randomised controlled trials are warranted to confirm the findings of this study. What this means at the molecular level is that the telomeric DNA contains binding sites for proteins that protect the end of the chromosome. Each ribozyme was delivered systemically after B16 cells had been introduced into mice by tail-vein injection. Telomerase is a critical factor in CAR-T cell replication and overall function, and its abundance diminishes in cell division, aging, and disease.With reduced telomerase activity, CAR-T cells typically die or become aged, non-functional, and non-proliferating (senescent), leading to inhibited CAR-T function and a lack of prolonged cancer . However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. The p53 response pathway is commonly abrogated in human cancers. Epub 2013 May 5. Yet that small fraction of the total telomerase that contained the mutant-template telomerase RNA was sufficient to elicit a robust apoptotic response. government site. Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). Delayed cancer detection is one of the common causes of poor prognosis in case of many cancers including the cancers of the oral cavity. The response to mutant-template telomerase RNA is highly specific for cells that have high levels of telomerase. 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. government site. Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJM, Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR, Blackburn EH. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. Federal government websites often end in .gov or .mil. 2022 Sep;22(9):515-532. doi: 10.1038/s41568-022-00490-1. Telomerase inhibitor BIBR1532 inhibits Kras, Figure 3. Telomerase therapy is a promising approach to treating age-related diseases. Epub 2018 Aug 2. Their telomeres are mostly maintained at a rather short length; the 40 kb telomeres in LOX melanoma cells are the exception rather than the rule. Epub 2013 Sep 17. 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. Tumor cells in control . The protein component of telomerase, telomerase reverse transcriptase (TERT), is indeed a protein enzyme and its amino acid sequence includes reverse transcriptase motifs. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). 2005;6:611622. 2019 Nov 15;105(4):861-874. doi: 10.1016/j.ijrobp.2019.08.009. This increased expression of telomerase makes it an attractive target for intervention. 4). FOIA (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. . KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. sharing sensitive information, make sure youre on a federal Careers. tumours. -, Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. 1999;97:50314. Would you like email updates of new search results? Instead, the affinity was increased by almost 3-fold as shown by the em K /em M values for the L-cysteine analog, RD-PNB (29 2.2 M) Mephenesin compared to the D-cysteine analog, L-70 (11 0.9 M). Increase Telomerase and Telomeres Naturally. -, de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . We found that the cellular response to this way of uncapping of telomeres in cancer cells was a very robust apoptotic response (Fig. Given this nding and the pilot nature of this study, we report . Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Psychoneuroendocrinology. 1998 Apr;102(4):397-402. doi: 10.1007/s004390050711. 2007;21(6):375-85. doi: 10.2165/00063030-200721060-00005. Clipboard, Search History, and several other advanced features are temporarily unavailable. . cancer cells employ . These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. 2022 Nov 7;10:1060201. doi: 10.3389/fcell.2022.1060201. Disclaimer, National Library of Medicine The Chemopreventive Activity of Indonesia Medicinal Plants Targeting on Hallmarks of Cancer. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. 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. Recent studies also suggest that telomerase is implicated in tumor progression in unexpected ways. Herein, an enzyme-free electroanal. Epub 2006 Mar 14. After much study, it has emerged that the RNAs from evolutionarily diverse eukaryotes share a common core structure (2). Interpretation Comprehensive lifestyle changes signi cantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity. Clipboard, Search History, and several other advanced features are temporarily unavailable. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and 3. Background: -, Eisenberg DT. 2009;361:23532365. 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. 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. I. Budunova. In the context of cancer cells, particularly those that are well on the way to a malignant state, telomerase has cancer-promoting properties. Cancer Ther 2 (2003): 209 -216. 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. As you might expect, telomerase is active in human stem cells and in germ line cells. Hence, the DNA at the ends of the chromosomes was effectively naked. The RNA has a short template sequence that is copied into DNA, which extends, and thus lengthens, the chromosomal DNA. The core structure includes a conserved pseudoknot, which is one of the parts of RNA that interact tightly and specifically with the protein TERT in the enzyme complex. Epigenetics alternation in lung fibrosis and lung cancer. Disclaimer, National Library of Medicine DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. We did these experiments in a manner that made the test of the effects as stringent as possible because we did not include a drug selection step after infecting the cells with the lentiviral vectors. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. 2008;14:57315734. 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. Please enable it to take advantage of the complete set of features! 5. The .gov means its official. In cell culture, telomere shortening leads to cell senescence as the telomeres no longer can sustain a capping structure at the ends of the chromosomes. 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. Nat Rev Genet. Authors have no potential conflicts of interest to disclose. Mutat Res. To determine whether the telomeres had become uncapped, we looked for the appearance of DNA damage foci at telomeres (Fig. Proc Am Thorac Soc. levels of TERT or telomerase activity (Fu et al., 2000). Li S, Rosenberg JE, Donjacour AA, et al. These observations lead us to investigate the most efficient means of inhibiting telomerase in cancer cells. Search for other works by this author on: Greider CW, Blackburn EH. Maciejewska N, Olszewski M, Jurasz J, Baginski M, Stasevych M, Zvarych V, Folini M, Zaffaroni N. Cell Death Dis. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. FOIA 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. The .gov means its official. 2). 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. This new gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression of 73 genes. Telomerase activity is essential for the maintenance of critical telomere length, enabling cell replicative immortality, one of the hallmarks of cancer . The results are the means SEM (n=3). Please enable it to take advantage of the complete set of features! Note: Although not eating fish is better for your telomeres, eating fish isn't necessarily bad for you. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH -. This is probably due to the all-encompassing anabolic effects of cellular growth caused by the main growth pathway in the body mTOR that will grow healthy cells but unfortunately sustains cancerous cells as well if they . Cell. Incorporation of nucleoside analogues into newly synthesized telomeres impairs POT1 binding, causing telomere dysfunction that elicits a DNA damage response and cell death. doi: 10.1093/nsr/nwaa306. This site uses cookies. An official website of the United States government. Epub 2022 Aug 16. Before 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. Would you like email updates of new search results? These experiments demonstrated that the telomerase RNA was being expressed in a way that supported its assembly into functional telomerase. In chronic lymphocytic leukemia cells, increased activity of the hypoxic pathway and ATM locus defects can render wild-type p53 hypophosphorylated. Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. -cancer cells show increased telomerase activity and the telomeres are not shortened. Disclaimer, National Library of Medicine 2009;6:201205. Nosrati M, Li S, Bagheri S, et al. 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. Xu L, Blackburn EH. This site needs JavaScript to work properly. [The 2009 Nobel Prize in Medicine and its surprising message: lifestyle is associated with telomerase activity]. The telomeres consist, first, of a DNA scaffold composed of a tract of very simple repeated DNA sequences. Mammalian telomeres end in a large duplex loop. Note: This lecture was presented at the AACR 96th Annual Meeting, April 16-20, 2005, Anaheim, CA, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California. We mutated the telomerase RNA template so that now a mutated DNA sequence was added to the chromosomes, directed by the mutated template. We therefore investigated what happens when you knock down the high levels of telomerase in human cancer cells. (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. HHS Vulnerability Disclosure, Help Identification of a specific telomere terminal transferase activity in. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Progressing next generation of telomere-targeting candidates through proof of concept studies with promising anti-cancer activity Filed provisional new composition of matter patent during fourth . Efficient platforms for detecting telomerase activity are essential for early tumor monitoring and diagnosis. Therapies that increase telomerase activity can also slow the rate of telomere shortening. Mutagenesis. Although in many normal adult human cell types telomerase is often expressed at very low, sometimes undetectable, levels, it is clear that telomerase has some protective role in such normal cells. Resulting in the overall . government site. Approximately 85% of human cancers achieve indefinite cell proliferation and avoidance of telomeric shortening through increased telomerase activity. Bethesda, MD 20894, Web Policies BioDrugs. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. 2000 Jan;462(1):31-47. doi: 10.1016/s1383-5742(99)00091-5. Accessibility Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. In bladder cancer, the promoter mutations correlate with increased TERT expression and telomerase enzymatic activity 21. Lin J, Ly H, Hussain A, et al. 1996;5:20716. Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches such as targeting TERT gene expression driven by TERT promoter mutations. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Telomerase is silenced in most normal cells but is active in an estimated 85% to 95% of human cancer cells. In 1998, Bodnar et al. Urol Oncol. Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a significantly increased risk of lung cancer compared to subjects with high telomerase activity (adjusted odds ratio = 3.05, 95% confidence interval = 1.60-5.82, P = 7 10(-4)). The activity of telomerase is relatively low in somatic cells and absent in normal cells, . While the mechanisms for telomerase activation in cancers have not been fully defined . PMC HHS Vulnerability Disclosure, Help Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. Also, Ground flax and chia seeds are excellent vegan sources of short-chain (ALA) omega-3s. The https:// ensures that you are connecting to the PMC Thus, incomplete replication of the chromosome ends occurs, which, if left unchecked by any compensatory mechanism, leads to a problem of maintaining the full-length of chromosomal DNA molecules. is the main cause for wide range of age-associated diseases like cancer, ischemic heart disease, stroke, type 2 diabetes, neurodegenerative diseases . Telomerase activity in hematopoietic cells is associated with self-renewal potential. Ashwagandha root extract increased telomerase activity with highest enhancement of ~45% at 10 - 50 g concentration. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3).
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