Extension of life span by introduction of telomerase into normal human cells. (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. 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)). Am J Hum Biol. FOIA 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. In control cells, the wild-type telomerase RNA was introduced, and big robust tumors formed. Telomerase reactivation causes aggressive cancer Third- and fourth-generation mice with telomerase activated by 4-OHT had a median survival of 30 days and more frequent tumor infiltration to the spleen, kidney, liver, lung, bone marrow and brain than did control-treated mice, 70 percent of which lived beyond 50 days. cancer cells employ . Similar to astragalus, extracts of cycloastragenol can increase telomerase activity. The replaced promotor E2F1 was specifically activated in Rb-defected tumor cells and hTERT promoters activated in telomerase-positive cancer cells increased the therapeutic efficacy of these OVs . Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Interpretation Comprehensive lifestyle changes signi cantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. 2009;361:23532365. Cancer research, 1995. However, the RNA is also critically important to the enzyme action, and not only because it provides the template. After much study, it has emerged that the RNAs from evolutionarily diverse eukaryotes share a common core structure (2). The site is secure. Epub 2006 Mar 14. Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. Immunity. Resulting in the overall . These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, P50 CA174523/CA/NCI NIH HHS/United States, P50CA174523/U.S. They hypothesized that this region was key to regulating telomerase activity and began to experiment on melanoma cells. Even people living in the Blue Zones eat fish in moderation. -, Calado RT, Young NS. Cell. [The 2009 Nobel Prize in Medicine and its surprising message: lifestyle is associated with telomerase activity]. This increased expression of telomerase makes it an attractive target for intervention. Epub 2022 Aug 16. This site needs JavaScript to work properly. Telomerase activity has been detected in 85% of tumors representing 15 cancer types, whereas most benign tumors and somatic tissues have very low levels or lack detectable telomerase activity Furthermore, in special metastatic tumor types such as neuroblastoma stage IVs, in which there is a high rate of spontaneous regression, telomerase . Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Thus far, everything discussed has related to telomerase acting in its familiar mode: making telomeric DNA longer. Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. (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. To determine whether the telomeres had become uncapped, we looked for the appearance of DNA damage foci at telomeres (Fig. 2011;23:149167. cancer cells employ . Bookshelf As a result, cancer cells essentially become immortal. Bethesda, MD 20894, Web Policies G-quadruplex (G4) stabilizers disrupt telomerase function by blocking the resolution of telomeric G-quadruplex DNA. The RNA has a short template sequence that is copied into DNA, which extends, and thus lengthens, the chromosomal DNA. 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. Cancer Ther 2 (2003): 209 -216. When compared with the parent cell line, in which the p53 locus is left intact, the responses between the lines were similar. 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. FOIA Gene Dev. Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. Rapid down-regulation of genes promoting cell cycle progression and metastasis. -cancer cells show increased telomerase activity and the telomeres are not shortened. Accessibility -. Epub 2019 Aug 13. The population of cells stably expressing the various different mutant-template RNAs at low levels could be cultured, although they grew very slowly. 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. 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. 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. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. Would you like email updates of new search results? Hence, our attempts to intervene in telomerase action have led us unexpectedly down a new avenue in which we find telomerase doing things that we never expected to see. Clipboard, Search History, and several other advanced features are temporarily unavailable. Copyright 2022 by the American Association for Cancer Research. eCollection 2022. In contrast to the effects of mutant-template telomerase RNA expression on telomerase RNA knockdown, no telomere shortening or telomere uncapping, or DNA damage response, accompanied the cell growth rate decrease. 2010 Jun 21;10:312. doi: 10.1186/1471-2407-10-312. sharing sensitive information, make sure youre on a federal 2010 Jun 13;151(24):965-70. doi: 10.1556/OH.2010.28899. We observed that at 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels of telomerase activity. 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. Kras mutations upregulate TERT expression and telomerase activities by the RAS-MEK pathway, Figure 2. That property also makes telomerase a very unusual reverse transcriptase. 2022 Sep;25(3):444-452. doi: 10.1038/s41391-022-00553-2. 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. Another study from the same group further clarified this potential link between telomerase expression and myofibroblast differentiation (18); using the same bleomycin-induced pulmonary fibrosis rat model, they demonstrated that the inhibition of fibroblast telomerase activity led to increased -SMA expression, which represents a marker of . PMC 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. Lancet Oncol. (7)]. tumours. 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. government site. Bookshelf 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). . Psychoneuroendocrinology. PMC 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. 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. MLL/AF4 suppression diminished telomerase activity and expression of TERT. -cancer . Telomere end-replication problem and cell aging. 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. FOIA Gupta N, Patel HD, Taylor J, Borin JF, Jacobsohn K, Kenfield SA, Eggener SE, Price C, Davuluri M, Byrne N, Bivalacqua TJ, Loeb S. Prostate Cancer Prostatic Dis. Therapies that increase telomerase activity can also slow the rate of telomere shortening. -, de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. While the mechanisms for telomerase activation in cancers have not been fully defined . A. Mutirangura, P. Supiyaphun, +4 . Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Telomerase play a key role in the maintenance of telomere length and chromosome integrity. This site needs JavaScript to work properly. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). 2002 Mar;2(1):1-17. doi: 10.2174/1568009023334015. I. Budunova. An official website of the United States government. HHS Vulnerability Disclosure, Help Telomerase is commonly expressed in human cancer cells. Mol. The Chemopreventive Activity of Indonesia Medicinal Plants Targeting on Hallmarks of Cancer. An official website of the United States government. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Recent work has confirmed these observations in both solid and hematopoietic cancers (5), leading to the proposal that telomerase expression may prove to be an important diagnostic tool as well as a novel target for cancer therapy. False. Before The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. 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. scientists may be able to stop cancer progression and potentially increase mortality. 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