Reproduced from The Journal of Cell Biology, 2004;167:819830 by copyright permission of The Rockefeller University Press (10). FOIA Incorporation of nucleoside analogues into newly synthesized telomeres impairs POT1 binding, causing telomere dysfunction that elicits a DNA damage response and cell death. Cell aging in relation to stress arousal and cardiovascular disease risk factors. I. Budunova. The https:// ensures that you are connecting to the The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. Xu L, Blackburn EH. Mammalian telomeres end in a large duplex loop. Targeting KRAS in NSCLC: Old Failures and New Options for "Non-G12c" Patients. 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)). This response does not require the telomeres to shorten. This increase coupled with the harsh side effects of some of the cancer chemotherapies have led to the search for more natural biological products, especially those derived from plant . Lancet Oncol. 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. Such a phospho-profile, termed profile II, cannot fully respond to DNA damage; accumulated p53 remains inactive and does not trigger transcription of its target genes upon stimulus, as compared to the standard phospho-profile I. Jacobs F, Cani M, Malapelle U, Novello S, Napoli VM, Bironzo P. Cancers (Basel). This inactive complex swamps out the endogenous telomerase. Findings: Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. Urol Oncol. And, indeed, many labs and many groups have now shown that the apparent increase in telomerase is a common feature of human tumor cells. Before 8600 Rockville Pike Clipboard, Search History, and several other advanced features are temporarily unavailable. These included some intriguing genes, such as cyclin G2 or CDC27genes that have been implicated in cell cycle progression. Disclaimer, National Library of Medicine Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase. Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. 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. Tumor cells in control . 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. Polymorphisms in telomere maintenance genes and risk of lung cancer. After 30 days, the tumor burden in the lungs, representing metastatic tumors in the lungs, was quantified. Clin Cancer Res. In 1998, Bodnar et al. Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. 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 . We used a particular cell line, the LOX human melanoma cell line, which happens to have particularly long telomeres, about 40 kb. . Am J Hum Biol. -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. eCollection 2021 Jun. Before An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. Hence, the telomeric structure is continually being assembled and disassembled. 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. 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. Mol Cancer Res 1 September 2005; 3 (9): 477482. Introduction. 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). PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression. A. Mutirangura, P. Supiyaphun, +4 . Semeraro MD, Almer G, Renner W, Gruber HJ, Herrmann M. Cells. Careers. 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. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. The results are the means SEM (n=3). The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction? In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. and transmitted securely. Please enable it to take advantage of the complete set of features! Please enable it to take advantage of the complete set of features! Cancer research, 1995. We were able to show that this also occurs in vivo. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. . Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres. Epub 2011 Jul 23. 2021 Jan 2;8(6):nwaa306. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. -, Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Careers. Before Targeting. PMC As a result, cancer cells essentially become immortal. 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 control cells, the wild-type telomerase RNA was introduced, and big robust tumors formed. Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. 2022 Oct 30;10(11):2755. doi: 10.3390/biomedicines10112755. Authors have no potential conflicts of interest to disclose. 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. Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. -, Blasco MA. 2022 Nov 7;10:1060201. doi: 10.3389/fcell.2022.1060201. Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats. Cancers (Basel). PMC Diminished telomerase activity by MMPL resulted in the suppression of both telomerase . The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. 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. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. Thus far, everything discussed has related to telomerase acting in its familiar mode: making telomeric DNA longer. 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). 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. An official website of the United States government. Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. HHS Vulnerability Disclosure, Help Yet that small fraction of the total telomerase that contained the mutant-template telomerase RNA was sufficient to elicit a robust apoptotic response. Bookshelf Thus, telomerase represents an attractive target for highly selective cancer therapeutics. 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. This study was published in the prestigious . Telomerase inhibitor BIBR1532 inhibits Kras mutations-induced cell transformation and migration capability, Figure 4. A universal telomerase RNA core structure includes structured motifs required for binding the telomerase reverse transcriptase protein. 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. The protein component of telomerase, telomerase reverse transcriptase (TERT), is indeed a protein enzyme and its amino acid sequence includes reverse transcriptase motifs. DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. Extension of life span by introduction of telomerase into normal human cells. Cell. 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. 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. -, Eisenberg DT. The site is secure. Weinstein IB. We therefore investigated what happens when you knock down the high levels of telomerase in human cancer cells. This implies that they have become adapted to their high levels of telomerase. It is in that latter context that we are interested in intervening in telomerase action. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. is the main cause for wide range of age-associated diseases like cancer, ischemic heart disease, stroke, type 2 diabetes, neurodegenerative diseases . Adv Pharm Bull. Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. Accessibility HHS Vulnerability Disclosure, Help Recent studies also suggest that telomerase is implicated in tumor progression in unexpected ways. 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. Although that experiment showed that with enough telomerase the telomeres can be maintained, the length at which they are maintained in a cell is the result of a complex interplay among many different factors. 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). 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). 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. But there are risks. Which of the following statements is accurate about the activity of the telomerase enzyme in cancer cells? it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity. Gene Dev. 2022 Oct 26;14(21):5257. doi: 10.3390/cancers14215257. Satisfied that the effects indeed resulted specifically from knockdown of the intended telomerase RNA, we analyzed the effects in multiple cell lines. 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 . 2005;19:21002110. An official website of the United States government. Enzymatic activity is a fundamental metric of telomerase. 2013;14:205214. 2009;361:23532365. Strategy for mutant telomere synthesis in human cancer cells. Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Telomerase inhibitor BIBR1532 increases sensitivities of Kras G12D and Kras G12V -Calu-3 cells, Figure 5. The RNA has a short template sequence that is copied into DNA, which extends, and thus lengthens, the chromosomal DNA. Would you like email updates of new search results? Liu Y, Betori RC, Pagacz J, Frost GB, Efimova EV, Wu D, Wolfgeher DJ, Bryan TM, Cohen SB, Scheidt KA, Kron SJ. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. . PubMed. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Bookshelf Recent studies also suggest that telomerase is implicated in tumor . The p53 response pathway is commonly abrogated in human cancers. The mutant-template telomerase RNA caused uncapping of the telomeres. Hence, the DNA at the ends of the chromosomes was effectively naked. Delay dependent on initial telomere length in the cancer cells? In humans, telomerase enzyme activity is absent in most normal cells but present in the majority of tumors (4). 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. Even people living in the Blue Zones eat fish in moderation. 4). Our data strengthens the relationship of the Wnt/-catenin pathway and telomere length in the pathogenesis of aCPs. 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. 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). 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