Targeting Shelterin via TRF1 to Degrade Telomeres in Cancer Cells

Cancer cells depend on lengthening their telomeres, usually via telomerase activity. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little length is lost with each cell division, and when short a cell either self-destructs or becomes senescent and ceases replication. Cancer cells can only replicate continually if telomeres are extended continually. Thus some research groups are looking into sabotage of telomerase or the alternative lengthening of telomeres (ALT) processes as the basis for a truly universal cancer therapy. Others, as here, are investigating ways to interfere in mechanisms that protect telomeres from degradation, hopefully obtaining much the same result in the end. In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers. In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuc...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs

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This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications. Gene Therapy in Mice Alters the Balance of Macrophage Phenotypes to Slow Atherosclerosis Progression https://www.fightaging.org/archives/2019/07/gene-therapy-in-mice-alters-the-balance-of-macrophage-phenotypes-to-slow-atherosclerosis-progression/ Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract Rs189037 (G>A) is an important functional variant with ataxia telangiectasia mutated ( ATM ) gene, which might affect ATM 's expression to involve in several human cancers. Increasing evidence reveals that smoking-related cancers have distinct molecular characteristics from non-smoking cancers. By now, the role of ATM rs189037 in cancer risk stratified by smoking status still remains unclear. To evaluate the association between ATM rs189037 and cancer risk based on smoking status, we performed this meta-analysis by a comprehensive literature search via databases of PubMed, Embase, Web of Science and CN...
Source: Bioscience Reports - Category: Biomedical Science Authors: Tags: Biosci Rep Source Type: research
Abstract Matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) contribute to metastasis. As shown in our previous studies, interleukin-6 (IL-6) induces ATM phosphorylation to increase MMP expression and metastasis in lung cancer. However, the exact roles of ATM activation in the IL-6-induced epithelial-mesenchymal transition and lung cancer metastasis are currently unclear. Here, ATM phosphorylation exerts its pro-metastatic effect via vimentin-mediated epithelial-mesenchymal transition, which was supported by the evidence described below. Firstly, IL-6 treatment increases vimentin expre...
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research
Alla S. Koltsova1,2, Anna A. Pendina1, Olga A. Efimova1*, Olga G. Chiryaeva1, Tatyana V. Kuznetzova1 and Vladislav S. Baranov1,2 1D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, Russia 2Department of Genetics and Biotechnology, Saint Petersburg State University, Saint Petersburg, Russia In the present review, we focus on the phenomenon of chromothripsis, a new type of complex chromosomal rearrangements. We discuss the challenges of chromothripsis detection and its distinction from other chromoanagenesis events. Along with already known causes and mechanisms, we introdu...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
In this study, T cells deficient in TRAF6 display enhanced T cell activation, CD28-indpendent stimulation and resistance to Treg cell-mediated suppression (176). Although TLR signaling can promote T cell resistance to Treg cells, the precise molecular mechanism remains yet to be elucidated. It is worth noting that TLR stimulation of T cells increases cytokine production (173, 177), thus future studies should delineate the effect of TLR-MyD88 signaling vs. subsequently induced cytokines in generating resistance to Treg cells. Lastly, it is also crucial to evaluate the effect of TLR signaling on regulatory T cells which also...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Discussion Suppressor of cytokine signaling 1 is an essential molecule for maintaining immune homeostasis and subverting inflammation. Disorders arising from excess inflammation or SOCS1 deficiency can be potentially treated with SOCS1 mimetics (Ahmed et al., 2015). While SOCS1 has promising potential in many disorders, it should be noted that new targets and actions of SOCS1 are still being discovered and not all the effects of this protein are beneficial in autoimmune diseases and cancer. For instance, SOCS1 degrades IRS1 and IRS2, required for insulin signaling, via the SOCS Box domain, thus, limiting its potential in ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
We describe the paraneoplastic neurological manifestations of patients with SCLC with and without SCLC‐predictive autoantibodies and the correlation between autoi mmunity and survival. We reviewed the records of 116 patients (51% male) from the Mayo Clinic with histopathologically confirmed SCLC for whom stored serum was available for neural autoantibody testing. Cancer was limited stage in 41%; the median age at diagnosis was 64 years. Paraneoplastic neuro logical manifestations were recorded in 61% (decreasing frequency: peripheral neuropathy, dysautonomia, cognitive decline, cerebellar ataxia, neuromuscular jun...
Source: Thoracic Cancer - Category: Cancer & Oncology Authors: Tags: BRIEF REPORT Source Type: research
Authors: Luo D, Dong XW, Yan B, Liu M, Xue TH, Liu H, You JH, Li F, Wang ZL, Chen ZN Abstract Natural killer (NK) cells recognize stress‑activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI‑H157 and NCI‑H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. The mechanism underlying the regulatory effect of ...
Source: Molecular Medicine Reports - Category: Molecular Biology Tags: Mol Med Rep Source Type: research
AbstractTo describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice forTrim9 and67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune en...
Source: The Cerebellum - Category: Neurology Source Type: research
Honnorat J Abstract To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 pat...
Source: Cerebellum - Category: Neuroscience Authors: Tags: Cerebellum Source Type: research
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