In the context of the human body, the fact that the action of telomerase allows cells to keep multiplying can have different kinds of consequences. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). 2022 Dec 6;23(23):15435. doi: 10.3390/ijms232315435. J. Mol. FOIA After 30 days, the tumor burden in the lungs, representing metastatic tumors in the lungs, was quantified. Epub 2012 Sep 10. 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). Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. 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. FOIA It is in that latter context that we are interested in intervening in telomerase action. The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. Strategy for mutant telomere synthesis in human cancer cells. Maciejewska N, Olszewski M, Jurasz J, Baginski M, Stasevych M, Zvarych V, Folini M, Zaffaroni N. Cell Death Dis. Immunotherapies - Peptide or DNA vaccines supply immunogenic TERT epitopes that stimulate immune responses against telomerase-expressing cancer cells. Curr Cancer Drug Targets. Bethesda, MD 20894, Web Policies MeSH Melanoma, an aggressive form of skin cancer, is highly dependent on telomerase to grow, . 2000 Jan;462(1):31-47. doi: 10.1016/s1383-5742(99)00091-5. The https:// ensures that you are connecting to the 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. We mutated the telomerase RNA template so that now a mutated DNA sequence was added to the chromosomes, directed by the mutated template. Cancers (Basel). Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Systematic review of the impact of a plant-based diet on prostate cancer incidence and outcomes. The expression of telomerase in various human cancers and its diminished expression in most normal cells suggest that the enzyme might serve as a good target for anticancer drugs. Too much telomerase can help confer immortality onto cancer cells and actually increase the likelihood of cancer, . 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. 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. Telomerase inhibitor BIBR1532 inhibits Kras, Figure 3. The accumulation of oxidative DNA base damage can severely disrupt the integrity of the genome and is strongly associated with the development of cancer. Lung Cancer; Susceptibility; Telomerase Activity. 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. Also, Ground flax and chia seeds are excellent vegan sources of short-chain (ALA) omega-3s. Clipboard, Search History, and several other advanced features are temporarily unavailable. Would you like email updates of new search results? In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. eCollection 2021 Jun. Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). 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). Kras mutations upregulate TERT expression and telomerase activities by the RAS-MEK pathway, Figure 2. Telomeres, telomerase, and myc. Approximately 85% of human cancers achieve indefinite cell proliferation and avoidance of telomeric shortening through increased telomerase activity. -, Blasco MA. 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. Liu Y, Betori RC, Pagacz J, Frost GB, Efimova EV, Wu D, Wolfgeher DJ, Bryan TM, Cohen SB, Scheidt KA, Kron SJ. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Semeraro MD, Almer G, Renner W, Gruber HJ, Herrmann M. Cells. CHICAGO--(BUSINESS WIRE)-- MAIA Biotechnology, Inc. (NYSE American: MAIA) announced today the advancement of its Telomere-Targeting Molecule Program ("Project T3").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 of these cells. 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). Li S, Crothers J, Haqq CM, Blackburn EH. Cell. He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. Accessibility 4. Clipboard, Search History, and several other advanced features are temporarily unavailable. Bookshelf Ashwagandha root extract increased telomerase activity with highest enhancement of ~45% at 10 - 50 g concentration. 2008 Jul;99(7):1385-9. doi: 10.1111/j.1349-7006.2008.00831.x. 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. 1). When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). Incorporation of nucleoside analogues into newly synthesized telomeres impairs POT1 binding, causing telomere dysfunction that elicits a DNA damage response and cell death. Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin's Lymphoma Cell Death. Bookshelf HHS Vulnerability Disclosure, Help The fruit fly Drosophila melanogaster . official website and that any information you provide is encrypted False. Clin Lung Cancer. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, R01CA226888/U.S. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. 13. When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). It is this addition of telomeric DNA in increments to the ends of chromosomes that offsets and counterbalances the shortening of chromosome ends. Epub 2019 Aug 13. 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. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and cancer cells employ . scientists may be able to stop cancer progression and potentially increase mortality. These observations lead us to investigate the most efficient means of inhibiting telomerase in cancer cells. Before Once again, the effects did not require p53 (7). Use of the D- in place of L-cysteine did not prevent hydrolysis by PMPMEase. 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. 2021 Dec 16;13(24):6332. doi: 10.3390/cancers13246332. Lin J, Ly H, Hussain A, et al. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. DNA damage foci accumulate at a subset of telomeres in cells expressing a mutant-template telomerase RNA. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. Gene Dev. These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. Thomas . 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. . Front Cell Dev Biol. 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. 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. Findings: Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. For example, up-regulation of p21 expression was seen, consistent with a DNA damage response. Copyright 2022 by the American Association for Cancer Research. 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. Nosrati M, Li S, Bagheri S, et al. (7)]. What this means at the molecular level is that the telomeric DNA contains binding sites for proteins that protect the end of the chromosome. BIBR1532, a Selective Telomerase Inhibitor, Enhances Radiosensitivity of Non-Small Cell Lung Cancer Through Increasing Telomere Dysfunction and ATM/CHK1 Inhibition. 3). HHS Vulnerability Disclosure, Help Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. eCollection 2021. Telomerase activity analysis was . Northern blot analysis of RNA extracted from a human cancer cell line, MCF-7. Prospects for anti-neoplastic therapies based on telomere biology. Methods: 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. At a Glance. Clin Cancer Res. 2009;6:201205. Telomerase therapy is a promising approach to treating age-related diseases. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Telomere length and the risk of lung cancer. Disclaimer, National Library of Medicine GFP lane, Northern blot analysis of RNA from cells expressing GFP alone from the control lentiviral vector [adapted from Li et al. 2. Please enable it to take advantage of the complete set of features! Careers. Hum Genet. Bodnar AG, Ouellette M, Frolkis M, et al. Background: signals of methylene blue (MB) catalyzed by well monodisperse Au nanorods (AuNRs). -. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. In one experiment, researchers blocked telomerase activity in human breast and prostate cancer cells growing in the laboratory, prompting the tumor cells to die. Please enable it to take advantage of the complete set of features! 2015;65:87108. FOIA 4. HHS Vulnerability Disclosure, Help Epub 2006 Mar 14. Clipboard, Search History, and several other advanced features are temporarily unavailable. As mentioned previously, if telomerase is present in sufficient amounts, it permits cells to keep multiplying. Please enable it to take advantage of the complete set of features! official website and that any information you provide is encrypted Figure 1. 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. Telomerase play a key role in the maintenance of telomere length and chromosome integrity. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Epub 2022 Oct 6. In 1998, Bodnar et al. 2006 Apr;31(3):277-87. doi: 10.1016/j.psyneuen.2005.08.011. This was first shown in a model organism, the ciliate Tetrahymena, and subsequently in many other organisms. Epub 2013 Sep 17. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. Targeting KRAS in NSCLC: Old Failures and New Options for "Non-G12c" Patients. Macek P, Poreba R, Gac P, Bogunia-Kubik K, Dratwa M, Wieckiewicz M, Wojakowska A, Michalek-Zrabkowska M, Mazur G, Martynowicz H. Biomedicines. Keywords: The template is only a minor part of the entire telomerase RNA molecule. Thus far, everything discussed has related to telomerase acting in its familiar mode: making telomeric DNA longer. Mol Oncol. Therefore, Shang Li developed a short-term expression system for mutant-template telomerase RNA (6). 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. Integrin V, which has been implicated in promoting tumor metastasis, was also suppressed. The RNA has a short template sequence that is copied into DNA, which extends, and thus lengthens, the chromosomal DNA. K01AT004199/AT/NCCIH NIH HHS/United States. 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)). 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. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. Cancer Sci. Telomeres are located at the ends of chromosomes and protect them from degradation. Dybiec J, Szlagor M, Mynarska E, Rysz J, Franczyk B. Int J Mol Sci. Cynthia Marcelo. 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 . 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. This had the consequence of leaving the telomeric tip uncapped (Fig. 2015 Apr 30;232(1):58-64. doi: 10.1016/j.pscychresns.2015.01.007. This site needs JavaScript to work properly. Not all cellsonly about 90% to 95% of the cellswere infected. Hence, such a p53-independent apoptotic response is desirable if one is interested in intervening in telomerase action as an anticancer approach. Wolkowitz OM, Mellon SH, Lindqvist D, Epel ES, Blackburn EH, Lin J, Reus VI, Burke H, Rosser R, Mahan L, Mackin S, Yang T, Weiner M, Mueller S. Psychiatry Res. MEK inhibition led to reduced TERT expression and telomerase activity. 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). And, indeed, many labs and many groups have now shown that the apparent increase in telomerase is a common feature of human tumor cells. Falus A, Marton I, Borbnyi E, Tahy A, Kardi P, Aradi J, Stauder A, Kopp M. Orv Hetil. Telomerase activity in oral leukoplakia and head and neck squamous cell carcinoma. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. The population of cells stably expressing the various different mutant-template RNAs at low levels could be cultured, although they grew very slowly. Epub 2022 Aug 16. We observed that at 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels of telomerase activity. In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. 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. Interpretation: 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. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. Hence, all one needed to do was spike the endogenous telomerase in the cancer cells with a little mutant-template telomerase RNA that assembled into the telomerase to make mutant repeats. Epub 2020 Feb 27. Even people living in the Blue Zones eat fish in moderation. 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. and transmitted securely. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. We expressed the telomerase RNA under a promoter that allowed telomerase to be expressed and active, even in cell lines that normally do not express any telomerase. Telomeres, the ends of the chromosomes, are required to protect chromosomal ends. Federal government websites often end in .gov or .mil. Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. 24 patients had sufficient PBMCs needed for longitudinal analysis. [The 2009 Nobel Prize in Medicine and its surprising message: lifestyle is associated with telomerase activity].
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