scholarly journals Cancer cells with alternative lengthening of telomeres do not display a general hypersensitivity to ATR inhibition

2016 ◽  
Author(s):  
Katharina I. Deeg ◽  
Inn Chung ◽  
Caroline Bauer ◽  
Karsten Rippe
Keyword(s):  
Cell Viability ◽  
Cancer Cells ◽  
Cell Lines ◽  
Ataxia Telangiectasia ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Isogenic Cell Line ◽  
Alternative Lengthening ◽  
Cellular Immortality ◽  
Proliferation Potential

AbstractTelomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT) pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anticancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia-and RAD3-related (ATR) protein inhibitors (Flynn et al., Science 347, 273). Here, we measured the response of various ALT or telomerase positive cell lines to the ATR inhibitor VE-821. In addition, we compared the effect of the inhibitor on cell viability in an isogenic cell line, in which ALT was active or suppressed. In these experiments a general ATR inhibitor sensitivity of cells with ALT could not be confirmed. We rather propose that the observed variations in sensitivity reflect differences between cell lines that are unrelated to ALT.

scholarly journals Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timothy P. Lippert ◽  
Paulina Marzec ◽  
Aurora I. Idilli ◽  
Grzegorz Sarek ◽  
Aleksandra Vancevska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Shortening ◽  
Alternative Lengthening ◽  
A Cell ◽  
Infected Cells ◽  
Break Induced Replication ◽  
Alt Activity

AbstractTo achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

scholarly journals Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sabine A. Hartlieb ◽  
Lina Sieverling ◽  
Michal Nadler-Holly ◽  
Matthias Ziehm ◽  
Umut H. Toprak ◽  
...  
Keyword(s):  
High Frequency ◽  
Clinical Course ◽  
Population Based ◽  
Telomeric Repeat ◽  
Telomere Maintenance ◽  
Study Cohort ◽  
Alternative Lengthening Of Telomeres ◽  
Course Of Disease ◽  
Low Protein ◽  
Alternative Lengthening

AbstractTelomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.

scholarly journals Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3790
Author(s):  
Gro Elise Rødland ◽  
Sissel Hauge ◽  
Grete Hasvold ◽  
Lilli T. E. Bay ◽  
Tine T. H. Raabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Viability ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Combined Treatment ◽  
Cancer Cell Lines ◽  
Variable Extent ◽  
Synergistic Induction

Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.

scholarly journals Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide

2021 ◽  
Author(s):  
Patricia Cámara-Sánchez ◽  
Zamira V. Díaz-Riascos ◽  
Natalia García-Aranda ◽  
Petra Gener ◽  
Joaquin Seras-Franzoso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Subtype ◽  
Anchorage Independent Growth ◽  
Tnbc Cell

Abstract Background Cancer maintenance, metastatic dissemination and drug-resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest numbers of CSCs and poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. Methods The anti-CSC efficacy of up to 17 small-drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness hallmarks were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes upon 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on the CSC proliferation and on stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSCenriched mammospheres. Finally, the efficacy of the NCS in combination with PTX was analyzed in vivo using an orthotopic mice model of MDA-MB-231 cells. Results Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8Q/PTX and NCS/PTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The solely use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination with 8Q and NCS counteracted this pro-CSC activity of PTX whilst significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth, and limited the dissemination of the disease by reducing the circulating tumor cells and the incidence of lung metastasis. Conclusions The combination of 8Q and NCS with PTX at established ratios inhibits both, the proliferation of differentiated cancer cells and the viability of CSCs, opening a way to more efficacious TNBC treatments.

C5-curcuminoid-dithiocarbamate based molecular hybrids: synthesis and anti-inflammatory and anti-cancer activity evaluation

RSC Advances ◽  
2014 ◽  
Vol 4 (54) ◽  
pp. 28756-28764 ◽  
Author(s):  
Amit Anthwal ◽  
Kundan Singh ◽  
M. S. M. Rawat ◽  
Amit K. Tyagi ◽  
Bharat B. Aggarwal ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Activity Evaluation ◽  
Anti Cancer ◽  
Molecular Hybrids ◽  
Anti Inflammatory ◽  
New Compounds ◽  
Cancer Activity ◽  
Proliferation Potential

The C5-curcumin-dithiocarbamate analogues were synthesized in search of new molecules with anti-proliferation potential against cancer cells. These new compounds demonstrated higher anti-proliferation and anti-inflammatory activity against cancer cell lines in comparison to curcumin.

scholarly journals Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway

2019 ◽  
Vol 5 (10) ◽  
pp. eaax6366 ◽  
Author(s):  
Mafei Xu ◽  
Jun Qin ◽  
Leiming Wang ◽  
Hui-Ju Lee ◽  
Chung-Yang Kao ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Direct Interaction ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Core Complex ◽  
Alternative Lengthening Of Telomeres ◽  
Independent Manner ◽  
Replication Complex ◽  
Alternative Lengthening ◽  
Key Steps

Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

scholarly journals The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 949 ◽  
Author(s):  
Marta Recagni ◽  
Joanna Bidzinska ◽  
Nadia Zaffaroni ◽  
Marco Folini
Keyword(s):  
Cancer Cells ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Limited Information ◽  
Adaptive Responses ◽  
Therapeutic Implications ◽  
Telomerase Inhibitors ◽  
Alternative Lengthening

Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients’ outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

scholarly journals ALT: A Multi-Faceted Phenomenon

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 133 ◽  
Author(s):  
Aurore Sommer ◽  
Nicola J. Royle
Keyword(s):  
Molecular Markers ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Sequence Variation ◽  
Telomere Maintenance ◽  
Hallmarks Of Cancer ◽  
Telomere Elongation ◽  
Maintenance Mechanism ◽  
Alternative Lengthening ◽  
Made In

One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.

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